R E V I E W
Leptin’s Role in Lipodystrophic and Nonlipodystrophic
Insulin-Resistant and Diabetic Individuals
Hyun-Seuk Moon,* Maria Dalamaga,* Sang-Yong Kim,* Stergios A. Polyzos,
Ole-Petter Hamnvik, Faidon Magkos, Jason Paruthi, and Christos S. Mantzoros
Division of Endocrinology, Diabetes, and Metabolism (H.-S.M., S.-Y.K., O.-P.H., F.M., J.P., C.S.M.), Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215; Department of Clinical
Biochemistry (M.D.), Attikon General University Hospital, Athens University Medical School, Athens 15784, Greece;
Division of Endocrinology and Metabolism (S.-Y.K.), School of Medicine, Chosun University, Gwang-Ju 501-717, South
Korea; Second Medical Clinic (S.A.P.), Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki 11527,
Greece; Division of Endocrinology, Diabetes, and Hypertension (O.-P.H.), Brigham and Women’s Hospital, Harvard
Medical School, Boston, Massachusetts 02115; and Section of Endocrinology (C.S.M.), Boston VA Healthcare System,
Harvard Medical School, Boston, Massachusetts 02118
Leptin is an adipocyte-secreted hormone that has been proposed to regulate energy homeostasis as well as metabolic, reproductive, neuroendocrine, and immune functions. In the context of open-label uncontrolled studies, leptin
administration has demonstrated insulin-sensitizing effects in patients with congenital lipodystrophy associated
with relative leptin deficiency. Leptin administration has also been shown to decrease central fat mass and improve
insulin sensitivity and fasting insulin and glucose levels in HIV-infected patients with highly active antiretroviral
therapy (HAART)-induced lipodystrophy, insulin resistance, and leptin deficiency. On the contrary, the effects of
leptin treatment in leptin-replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. Similarly,
experimental evidence suggests a null or a possibly adverse role of leptin treatment in nonlipodystrophic patients
with nonalcoholic fatty liver disease. In this review, we present a description of leptin biology and signaling; we
summarize leptin’s contribution to glucose metabolism in animals and humans in vitro, ex vivo, and in vivo; and we
provide insights into the emerging clinical applications and therapeutic uses of leptin in humans with lipodystrophy
and/or diabetes. (Endocrine Reviews 34: 377–412, 2013)
I. Introduction
II. Leptin Biology
A. Leptin discovery
B. Leptin production and circulation
C. Leptin receptors
D. Leptin’s antisteatotic and antilipotoxic role
E. Leptin’s role in glucose homeostasis
F. Leptin’s role in immune modulation
III. Leptin Signaling
A. Leptin and JAK2/STAT3/STAT5 signaling
B. Leptin and AMPK signaling
C. Leptin and PI3K/Akt/mTOR signaling
D. Leptin and FoxO1 signaling
E. Leptin and SHP2/MAPK signaling
F. Leptin and JAK2-independent signaling
IV. Leptin and Insulin Signaling
V. Leptin Resistance or Tolerance
A. Impaired activation of leptin receptor signaling/
inhibitors of leptin signaling
ISSN Print 0163-769X ISSN Online 1945-7189
Printed in U.S.A.
Copyright © 2013 by The Endocrine Society
Received August 22, 2012. Accepted January 2, 2013.
First Published Online March 8, 2013
doi: 10.1210/er.2012-1053
B. Impaired leptin transport across the BBB
C. Impaired ObRb trafficking
D. ER stress
E. Saturable nature of leptin signaling pathways
F. Impaired leptin neural circuitry
VI. Effects of Leptin on Glucose Metabolism in Animals
and Humans
* H.-S.M., M.D., and S.-Y.K. contributed equally to this work.
Abbreviations: ACC, acetyl-coenzyme A carboxylase; AgRP, agouti-related protein; ARC, arcuate nucleus; AMPK, AMP-activated protein kinase; BDNF, brain-derived neurotrophic factor;
BBB, blood-brain barrier; BMI, body mass index; CaMKK2, Ca2⫹/calmodulin-dependent protein kinase; CC, colorectal cancer; CNS, central nervous system; CoA, coenzyme A; DIO, dietinduced obesity; ER, endoplasmic reticulum; FoxO1, Forkhead box O1; GTT, glucose tolerance
test; HALS, HIV-associated lipodystrophy syndrome; hAT, human adipose tissue; HbA1C, glycated hemoglobin; HAART, highly active antiretroviral therapy; HFD, high-fat diet; HOMA,
homeostatic model assessment; HA, hypothalamic amenorrhea; HSC, hepatic stellate cell; icv,
intracerebroventricular; IKK␤, inhibitor of nuclear factor-␬B kinase subunit ␤; IRS, insulin receptor substrate; JAK2, Janus kinase 2; JNK, c-Jun N-terminal kinase; LDL, low-density lipoprotein; MC3R, melanocortin-3 receptor; mTOR, mammalian target of rapamycin; NAFLD,
nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NF-␬B, nuclear factor-␬B;
NPY, neuropeptide Y; ObR, obese receptor; P13K, phosphatidylinositol 3-kinase; PBMC, peripheral blood mononuclear cell; POMC, proopiomelanocortin; PPAR␥, peroxisome proliferator-activator receptor-␥; PTP, protein tyrosine phosphatase; SH2, Src homology-2; SH2B1,
SH2B adaptor protein 1; SHP2, SH2-containing protein tyrosine phosphatase 2; sOB-R, soluble
leptin receptor; SOCS3, suppressor of cytokine signaling 3; SS, simple steatosis; STAT3, signal
transducer and activator of transcription 3; STZ, streptozotocin; TG, triglyceride; Th, T helper;
UPR, unfolded protein response; VMH, ventromedial hypothalamus.
Endocrine Reviews, June 2013, 34(3):377– 412
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Effects of Leptin on Glucose Metabolism
A. States of leptin deficiency
B. States of leptin excess
C. Benefits, potential adverse effects, and challenges
in relation to leptin administration
VII. Future Directions
I. Introduction
eptin has a crucial role in the regulation of energy homeostasis, insulin action and lipid metabolism (1). As
a hormone secreted by adipocytes in quantities mainly
correlated with fat cell mass, leptin serves as an important
signal of body energy stores. Its importance is well illustrated by the physiological consequences of leptin deficiency in mice homozygous for a mutation in the obese
(ob) gene, which prevents leptin production or leads to
secretion of a truncated inactive leptin molecule (1–3).
Ob/ob mice exhibit hyperphagia, early-onset obesity, insulin resistance, diabetes (1, 2), and several neuroendocrine abnormalities (3, 4). All these abnormalities can be
corrected by exogenous leptin administration (1, 2, 5, 6),
suggesting that leptin plays a role in glucose homeostasis
and possibly in the pathogenesis of other obesity-related
metabolic complications. Interestingly, leptin-induced
normalization of hyperglycemia and hyperinsulinemia
in ob/ob mice is observed even before body weight reduction, suggesting that leptin’s effects on glucose homeostasis are, in part, independent of its weight-reducing effects (5, 6). Similar to ob/ob mice, other mouse
models of obesity and leptin resistance or tolerance
(7–9) present abnormalities of leptin deficiency due to
subnormal leptin action (7, 10, 11).
The importance of leptin is also evident in human physiology (3, 4, 7–18). Leptin administration has been demonstrated to successfully treat obesity and its complications in individuals with congenital leptin deficiency, and
thus, leptin is available on a compassionate basis for these
patients (5–7). Moreover, leptin is effective in correcting
neuroendocrine abnormalities and insulin resistance in
patients with HIV-associated lipodystrophy (11–13) and
congenital lipodystrophy (8 –10). Therefore, an application has been submitted to the U.S. Food and Drug Administration (FDA) for approval of leptin in replacement
doses for the treatment of congenital lipodystrophy. In
contrast, in subjects with garden-variety obesity or diabetes (who exhibit hyperleptinemia presumably due to leptin
tolerance), treatment with additional exogenous leptin
has not been associated with significant weight loss or
reduction in metabolic complications (19 –21). This suggests that leptin tolerance or resistance exists in these subjects (22, 23). Hence, although great progress has been
made in understanding the role of leptin in many physio-
L
Endocrine Reviews, June 2013, 34(3):377– 412
logical systems, much research is currently being directed
toward elucidating the mechanisms and pathophysiology
of leptin’s effects on glucose metabolism. In this review, we
describe the effects of leptin biology and signaling on glucose metabolism in animals and humans in vitro, ex vivo,
and in vivo and provide novel insights into emerging clinical applications and therapeutic uses of recombinant leptin in the area of lipodystrophy, insulin resistance, and
diabetes in humans.
II. Leptin Biology
A. Leptin discovery
In 1994, the mouse ob gene was found to encode a
16-kDa 167–amino-acid secreted protein with a 4-helix
bundle motif similar to that of a cytokine, which was
named leptin (from the Greek word leptos, meaning thin)
(10, 24). Leptin signals primarily the status of body energy
reserves in fat to the brain and other tissues so that appropriate changes in food intake, energy expenditure, and
nutrient partitioning can occur to maintain whole-body
energy balance (24). This system is especially sensitive to
energy deprivation. The discovery of leptin in 1995 also
defined a novel endocrine role for adipose tissue and thus
subsequently increased our understanding of how food
intake and energy metabolism are regulated (10).
B. Leptin production and circulation
Leptin is primarily produced in adipose tissue but is also
expressed in many other tissues, including the placenta,
mammary gland, testes, ovary, endometrium, stomach,
hypothalamus, pituitary, and others (25). Leptin concentrations in blood are pulsatile and follow a circadian
rhythm, with lowest levels in the early to midafternoon
and highest levels between midnight and early morning
(26). The pulsatile characteristics of leptin secretion are
similar in lean and obese individuals with the exception
that the obese exhibit higher pulse amplitudes of leptin
(26). Circulating leptin levels are directly proportional to
the amount of body fat (23) and fluctuate with acute
changes in caloric intake (27). Women tend to have higher
leptin concentrations than men, although a significant reduction in the amount of circulating leptin occurs after
menopause (28). This sexual dimorphism, which is independent of body mass index (BMI), is partly attributed to
differences in fat mass, body fat distribution, and sex hormones (29). Subcutaneous fat expresses more leptin
mRNA than omental (visceral) fat, and this may partially
contribute to higher leptin levels in women compared with
men (29). Thus, compared with visceral fat, accumulation
of sc fat is associated with higher leptin levels (26) and
steatotic and lipotoxic complications appear more fre-
doi: 10.1210/er.2012-1053
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quently in visceral obesity (27). Table 1 depicts factors that
affect circulating leptin levels in humans.
C. Leptin receptors
Leptin exerts its effects via binding to specific leptin
receptors (obese receptors [ObRs]) located throughout the
central nervous system (CNS), including the hypothalamus, and several peripheral organs (4, 10, 28). The leptin
receptor is a receptor in the class 1 cytokine receptor family, with a single membrane-spanning domain (10, 24, 28,
29). At present, 6 ObR isoforms, produced by alternative
splicing of the leptin receptor gene, have been identified in
rats (ObRa–ObRf) (30). In mice and humans, only 5
(ObRa–ObRe) and 4 (ObRa–ObRd) alternative spliced
isoforms have been described, respectively (30, 31). These
isoforms present homologous extracellular leptin-binding
domains but distinct intracellular domains varying in
length and sequence due to alternative mRNA splicing
(32). The short isoforms ObRa and ObRc may play an
important role in transporting leptin across the bloodbrain barrier (BBB) (32).
The long leptin receptor isoform, ObRb, which contains a full-length intracellular domain required for cell
signal transduction, is primarily responsible for leptin signaling (30, 31, 33) (Figure 1). ObRb is strongly expressed
throughout the CNS and particularly in the hypothalamus, where it regulates energy homeostasis (food intake
and energy expenditure) and neuroendocrine function
(30, 32–35). In the db/db mouse model, the ObRb is dysfunctional, resulting in obesity and the metabolic syndrome (36). ObRb mRNA is highly expressed in the hypothalamus, particularly in the arcuate nucleus (ARC), the
ventromedial hypothalamus (VMH), the lateral hypothalamic area, the dorsomedial hypothalamus (DMH), and
the ventral premammillary nucleus (32). Via its receptor,
leptin directly targets hypothalamic neurons, particularly
ARC neurons (proopiomelanocortin [POMC] and agoutirelated protein [AgRP] neurons), which are critical mediators of leptin action (37). POMC neurons are anorexigenic (appetite suppressor) neurons coexpressing POMC
Table 1.
and cocaine- and amphetamine-regulated transcript. After
proteolytic cleavage, POMC generates ␣-MSH, which
stimulates melanocortin-3 and -4 receptors (MC3R and
MC4R), which are important in energy homeostasis (37).
Genetic defects in the melanocortin system (POMC or
MCR genes) are related to obesity in humans (38). Conversely, AgRP neurons are orexigenic (appetite stimulator) neurons that inhibit POMC activity by releasing inhibitory ␥-aminobutyric acid and coexpress the orexigenic
AgRP and neuropeptide Y (NPY), antagonists of both
MC3R and MC4R (39). Leptin inhibits AgRP/NPY expression and AgRP neuronal excitability as well as ␥-aminobutyric acid release from AgRP neurons (39). Moreover,
in the VMH, leptin stimulates the expression of anorexigenic brain-derived neurotrophic factor (BDNF) through
MC4R signaling (40). Finally, in the hypothalamus, leptin
acts on neurons that directly or indirectly regulate levels of
other circulating hormones (eg, thyroid hormone, sex steroids, and GH) (30, 32, 33, 41). Leptin action on these
hypothalamic neurons also controls the activity of the autonomic nervous system; direct effects of leptin on ObRbcontaining neurons in the brainstem and elsewhere may
also play an important role (31, 33).
ObRb is also expressed in multiple peripheral tissues,
including pancreatic islets, adipose tissue, skeletal muscle,
liver, and immune cells (36, 37, 42). In the pancreatic
islets, leptin directly inhibits insulin expression and secretion (42). In liver and white adipose tissue, leptin inhibits
lipogenesis and stimulates lipolysis (36, 37) and adipocyte-specific overexpression of ObRb prevents dietinduced obesity (DIO) in mice (38). Leptin directly promotes fatty acid oxidation in isolated adipocytes and skeletal muscle (39, 40) and decreases lipid levels in isolated
livers (43). Liver-specific overexpression of ObRb prevents hepatic steatosis in ObR-deficient fa/fa rats (44, 45).
However, deletion of the ObRb in these peripheral tissues
has no effect on energy balance, body weight, or glucose
homeostasis in mice, indicating that these processes are
Factors That Regulate Serum Leptin Levels
Factors Promoting Leptin Secretion
a
Excess energy stored as fat (obesity)
Overfeedinga
Glucose
Amino acids
Insulin
Glucocorticoids
Estrogens
Inflammatory cytokines TNF-␣ and IL-6 (acute effect)
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Factors Inhibiting Leptin Secretion
Low energy states with decreased fat stored (leanness)a
Fastinga
Thyroid hormones
Free fatty acids and other lipid metabolites
Catecholamines and adrenergic agonists
Androgens
PPAR␥ agonistsb
Inflammatory cytokine TNF-␣ (prolonged effect)
a
Denotes major factor influencing leptin levels.
b
Unlike animals, PPAR␥ agonists in humans decrease leptin gene expression but increase sc fat mass, thus presenting a null effect.
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Endocrine Reviews, June 2013, 34(3):377– 412
Figure 1.
Figure 1. Intracellular signaling pathways recruited by leptin. The full-length isoform, ObRb, contains intracellular motifs required for activation of
the JAK2/STAT3 signal transduction pathway. ObRb contains 4 important tyrosine residues that provide docking sites for signaling proteins with
SHP2 domains. Activation of JAK2 occurs by transphosphorylation and subsequent phosphorylation of tyrosine residues in the cytoplasmic region
of the receptor. Phosphorylation of STAT3 leads to their dissociation from the receptor and the formation of active dimers, which translocate to
the nucleus to regulate gene expression, binding to the promoter regions of target genes. The leptin-regulated STAT3 signaling may interact with
STAT5, which may regulate STAT3-dependent gene expression. The ability of SOCS3 to inhibit leptin-stimulated phosphorylation of JAK2 provides
a negative-feedback mechanism on the leptin signaling system. The ERK members of the MAPK family are components of the well-defined AMPKRas/Raf/MAPK signaling cascade and have become activated by leptin. Leptin activates PI3K signaling via IRS-1 and/or IRS-2 phosphorylation. The
PTP1B inhibits leptin-stimulated phosphorylation of IRS-1/2 and/or JAK2. Leptin administration results further in Akt/mTOR phosphorylation
followed by regulation of FOXO and S6 expression.
mainly regulated by the central effects of leptin in the
brain (46).
D. Leptin’s antisteatotic and antilipotoxicity role
Whenever leptin action is not present either due to hypoleptinemia or leptin resistance, overfeeding could lead
to fat deposition to nonadipose tissues characterized by
generalized steatosis, lipotoxicity, and lipoapoptosis.
Generalized steatosis leading to a dysfunction of nonadipose tissues, ie, lipotoxicity, may affect pancreatic ␤-cells
(47, 48), myocardium (49), liver, kidneys, skeletal muscle
(50), and other nonadipose tissues (27). When there is
ectopic lipid accumulation during overfeeding, the surplus
of fatty acids follows the nonoxidative metabolic pathway
resulting in metabolic trauma characterized by lipotoxicity and lipoapoptosis (51). Also, apoptosis results from
excessive ceramide synthesis coupled with underexpression of the antiapoptotic factor bcl-2 (52). Ceramidotoxicity, which is not clearly identified in metabolic syndrome, has been shown to occur spontaneously in the
pancreatic islets of Zucker diabetic fatty (ZDF) rodents
with type 2 diabetes and metabolic syndrome (53). In humans, the constellation of lipotoxic abnorrmalities that
leads to insulin resistance, type 2 diabetes mellitus, and
fatty liver is referred to as the metabolic syndrome, suggesting that this syndrome includes lipotoxicity of pancreatic
␤-cells, liver, myocardium, and skeletal muscle in a manner
similar to lipotoxicity observed in rodents (27, 54, 55).
doi: 10.1210/er.2012-1053
Leptin constitutes a liporegulatory hormone that controls lipid homeostasis in nonadipose tissues particularly
during periods of overfeeding (27). It has been suggested
that leptin regulates intracellular fatty acid homeostasis
and prevents tissues from lipotoxicity, similar to insulin,
which regulates intracellular glucose homeostasis and prevents glucotoxicity (56). Leptin activates AMP-activated
protein kinase (AMPK), arresting lipogenesis and promoting fatty acid oxidation by inactivating acetyl coenzyme A
(CoA) carboxylase (ACC) (99). In nonobese diabetic mice
with uncontrolled diabetes type 1, leptin therapy normalizes the levels of a wide array of hepatic intermediary metabolites comprising acylcarnitines, tricarboxyl acid cycle
intermediates, amino acids, and acyl CoAs (58). Leptin
reduces both lipogenic and cholesterologenic transcription factors and enzymes and lowers plasma and tissues
lipids (58).
E. Leptin’s role in glucose homeostasis
Leptin may also directly regulate glucose homeostasis
independently of its effects on adiposity; leptin regulates
glycemia at least in part via the CNS, but it may also directly regulate the physiology of pancreatic ␤-cells (59, 60)
and peripheral insulin-sensitive tissues (61, 62). Low
doses of leptin that do not reduce food intake and body
weight almost normalize the severe hyperglycemia observed in ob/ob mice, demonstrating that leptin actions in
glucose homeostasis are independent from its actions in
food intake and body weight (2). In the context of severe
obesity and insulin resistance, the potent leptin actions in
glucose homeostasis are predominantly mediated by
POMC-expressing neurons within the arcuate nucleus of
the hypothalamus (64), although the AgRP-expressing
neurons and other hypothalamic and extrahypothalamic
neurons may also have important roles (65).
Recent studies have shown remarkable antidiabetic
properties of leptin as a powerful suppressor of glucagon
(58, 66, 67). Leptin suppresses glucagon hypersecretion in
rodents with diabetes type 1 at least as effectively as somatostatin and insulin, without producing undesirable
adverse effects (58, 67, 68). Administration of recombinant leptin to mice with uncontrolled diabetes type 1 reversed the catabolic syndrome in a similar manner as insulin did. Moreover, when leptin was added to low-dose
insulin therapy at 10% of the optimal dose, the volatility
of insulin monotherapy disappeared (58). This leptin
action was ascribed to the tonic suppression of hyperglucagonemia, affecting hyperglycemia (66). The antihyperglycemic, glucagon-suppressing action of peripherally administered leptin has been duplicated via leptin infusion into the
intracerebral ventricle (68). Therefore, leptin suppresses
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␣-cells directly or via a leptin-responsive hypothalamic pathway for glucagon production or both (66, 69).
Diabetes type 1 is characterized by loss of the endocrine
and paracrine functions of insulin. ␣-Cells lack constant
regulation of high insulin levels from juxtaposed ␤-cells
and hypersecrete glucagon, which causes directly diabetic
symptomatology (70). It has been proposed that insulin
monotherapy corrects the endocrine insulin deficiency but
may not fully correct the paracrine insulin deficiency that
is responsible for the glycemic volatility and the catabolic
syndrome of diabetes type 1 (66). If glucagon hypersecretion is the major cause of metabolic aberrations in human
diabetes, glucagon inactivation or suppression could provide an attractive therapeutic vista for managing diabetic
symptomatology compared with insulin monotherapy.
F. Leptin’s role in immune modulation
Leptin presents a pivotal role in the modulation of immune function. In normal subjects, leptin’s role is associated with a balance between the number of T helper (Th)1
cells and Th2/Treg (regulatory T cells), which are able to
suppress immune and autoimmune responses (71). On one
hand, leptin contributes to protection from infectious diseases whereas on the other hand to loss of tolerance and
autoimmunity. Studies in mice have shown that effects of
leptin on the immune system are implemented via central
or peripheral pathways (72, 73). Leptin plays a role in the
cells belonging to both the innate and the adaptive immune
responses. In fact, as a cytokine, leptin affects thymic homeostasis and promotes Th1-cell immune responses by
increasing interferon-␥, tumor necrosis factor (TNF)-␣,
and IgG2a production from B cells (74). Leptin is involved
in all processes of NK cell development, differentiation,
proliferation, activation and cytotoxicity (75). Leptin constitutes a negative signal for the expansion of naturally
occurring human Foxp3⫹CD4⫹CD25⫺ regulatory T cells
(Treg), a cellular subset suppressing autoreactive responses mediated by CD4⫹CD25⫺ T cells (76). Hypo- and
aleptinemia results in impaired Th1 response and induction of Treg cells; reducing thus the immunocompetence
and autoimmunity in mice and humans and increasing
susceptibility to infections such as tuberculosis (TB), pneumonia, candidiasis, and bacterial and viral diarrhea (77–
79). Conversely, hyperleptinemia and leptin resistance are
associated with a low proportion and proliferation of Treg
cells, an expansion of Th1 cells and increased secretion of
proinflammatory cytokines that sustain and enhance the
development of immunoinflammatory responses and autoimmune diseases in subjects with predisposition to autoimmunity (72).
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Effects of Leptin on Glucose Metabolism
III. Leptin Signaling
A. Leptin and JAK2/STAT3/STAT5 signaling
It has been shown that ObRb activates a cascade of
several signal transduction pathways, including Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) (58) (Table 2 and Figure 1). The STAT
family comprises Src homology-2 (SH2) domain-containing
transcription factors situated in the cytoplasm in quiescent
cells. STAT activation results in homo- or heterodimerization, nuclear translocation, and transcriptional activation.
STAT3 is a transcription factor that is encoded by the STAT3
gene in humans (80). It mediates the expression of a variety
of genes in response to cell stimuli and thus plays a key role
in many cellular processes such as cell growth and apoptosis
(80, 81). Constitutive STAT3 activation is associated with
various human cancers and indicates poor prognosis, suggesting that STAT3 has antiapoptotic and proliferative effects (82– 84). In contrast, loss-of-function mutations in the
STAT3 gene result in hyper-IgE syndrome, associated with
recurrent infections as well as disordered bone and tooth
development (85, 86).
Table 2.
Endocrine Reviews, June 2013, 34(3):377– 412
The JAK2/STAT3 pathway is the first identified signaling mechanism associated with the leptin receptor and
plays a pivotal role in energy homeostasis and neuroendocrine function (80, 81, 84) (Table 2 and Figure 1). It
has been well established that leptin stimulates ObRb
dimerization, which results in JAK2 activation, autophosphorylation, and phosphorylation of Tyr985, Tyr1077, and
Tyr1138, which act as docking sites for key downstream
signaling molecules (59). Also, in response to leptin,
STAT3 binds to phospho-Tyr1138, allowing JAK2 to phosphorylate and stimulate STAT3. Leptin binds to its ObRb
receptor and activates the JAK2/STAT3 pathway in the
ARC of the hypothalamus, inducing the transcription of
the anorexigenic POMC and suppressing the orexigenic
AgRP/NPY (65). Moreover, leptin administration induces
phosphorylation of JAK2/STAT3 in several cell lines including keratinocytes, endometrial cancer cells, murine
adipocytes, and mouse adipose tissue (87). We have recently demonstrated for the first time that leptin activates
STAT3 signaling in mouse GT1-7 hypothalamic, C2C12
muscle, and AML12 liver cell lines (19). Also, we have
Main Signaling Pathways, Main Sites of Action, and Main Effects of Activation by Leptina
Signaling
Pathway
JAK2/STAT3
Primary Site of Action
Effects
Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates appetite, energy balance, and body weight
Regulates neuroendocrine function
Regulates cell proliferation
Regulates cell growth and apoptosis
Regulates bone and tooth development
STAT5
Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates energy balance and body weight
Regulates oncogenesis
MAPK
Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates appetite and body weight
Regulates fatty acid oxidation
Regulates cell hypertrophy
Regulates cell proliferation and differentiation
AMPK
Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates appetite, energy balance, and body weight
Regulates gluconeogenesis and energy homeostasis
Regulates fatty acid oxidation
Regulates insulin resistance
Regulates cell proliferation and survival
Regulates oncogenesis
PI3K/Akt/mTOR Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates appetite, fuel balance, and body weight
Regulates insulin/leptin resistance
Regulates sympathetic outflow
Regulates neuroendocrine function
Regulates adiposity and glucose homeostasis
Regulates cell proliferation
FoxO1
Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates appetite and body weight
Regulates energy expenditure
Regulates cell proliferation and differentiation
Regulates insulin signaling
SHP2/MAPK
Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates appetite and body weight
Regulates STAT3 signaling with SOCS3
Regulates mitosis, proliferation, and differentiation
Regulates cell apoptosis and survival
Regulates neuroendocrine function
a
Adapted from Refs. 3 and 19 –21.
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383
demonstrated that leptin activates STAT3 signaling in human adipose tissue (hAT) in vivo and ex vivo and in human
primary adipocytes in vitro (20, 21). Conversely, disrupting the ability of the leptin receptor to activate the STAT3
pathway in mice leads to severe obesity and several neuroendocrine abnormalities including decreased linear
growth and infertility (88).
Leptin may also activate phosphorylation of ObRb on
Tyr1077, which binds to STAT5 and stimulates STAT5
phosphorylation (32) (Figure 1). STAT5 deletion in the
brain causes hyperphagia and obesity to a lesser extent
than STAT3 deletion, suggesting that the ObRb/JAK2/
STAT5 pathway may also play a role in the regulation
of body weight and energy balance by leptin (70) (Table
2). It is important to study in depth the effects of leptin
on human hypothalamic or other CNS cells; leptinincreased STAT3/STAT5 signaling in several tissues
and cells may have important clinical implications including oncogenesis.
drome in hypoleptinemic humans (99, 100), thus supporting the potential use of leptin in treating lipodystrophy
and, possibly, obesity and type 2 diabetes.
In contrast to its actions in muscle, leptin has been
shown to exert an inhibitory effect on AMPK in the hypothalamus that results in stimulation of the hypothalamic ACC and subsequent reduction of food intake and
weight gain (86). Leptin’s hypothalamic effects on AMPK
are in part mediated by the MC4R pathway, which promotes anorexia (86). Moreover, the Ca2⫹/calmodulindependent protein kinase (CaMKK2) is an upstream activator of AMPK in the hypothalamus, whereas CAMKK2
inhibition reduces appetite and body weight (88). These
observations indicate that the hypothalamic CaMKK2/
AMPK/ACC pathway may also mediate leptin’s anorexigenic action. Further in vivo studies in humans are needed
to elucidate whether leptin administration may alter in
vivo signaling by altering a third intermediate factor that
possibly could not be studied in vitro.
B. Leptin and AMPK signaling
C. Leptin and PI3K/Akt/mTOR signaling
AMPK is an evolutionarily conserved serine/threonine protein kinase central to the regulation of cell
growth, proliferation, differentiation, motility, and survival (71) (Table 2 and Figure 1). AMPK is considered
a cellular energy sensor that is stimulated by an increase
in the intracellular AMP to ATP ratio (71). In its classical role as an intracellular metabolic stress-sensing
kinase, AMPK switches on fatty acid oxidation and glucose uptake while switching off hepatic gluconeogenesis. It also exerts a broader role in metabolism by controlling appetite (89, 90). AMPK is also involved in
cellular energy homeostasis through AMPK phosphorylation and inhibition of ACC, thus stimulating fatty
acid oxidation (91–93).
Leptin’s actions in peripheral tissues are partly due to its
effects on AMPK, which contribute to leptin’s effects on
fatty acid oxidation and glucose uptake (94). In mouse
skeletal muscle, leptin activates AMPK, which leads to
phosphorylation and inhibition of ACC and subsequent
stimulation of fatty acid oxidation. There appear to be 2
mechanisms through which leptin activates AMPK in
muscle (95, 96). One pathway involves the hypothalamus
including the ␣-adrenergic pathway, resulting in a prolonged effect, and as shown in our previous ex vivo and in
vitro experiments (84), the second mechanism encompasses leptin’s direct effect on skeletal muscle. The ability
of leptin to stimulate fatty acid oxidation in skeletal muscle, which plays a pivotal role in the pathophysiology of
insulin resistance (97, 98), may prevent lipotoxicity and
subsequent insulin resistance and may underlie leptin’s
ability to improve insulin resistance and metabolic syn-
Phosphatidylinositol-3 kinase (PI3K) has been linked
to an extraordinarily diverse group of cellular functions,
including cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking (101–103)
(Table 2 and Figure 1). These functions are related to the
ability of class I PI3Ks, which are responsible for the production of phosphatidylinositol 3-phosphate, phosphatidylinositol (3,4)-bisphosphate, and phosphatidylinositol
(3,4,5)-trisphosphate, to modulate protein kinase B, suggesting that PI3K/Akt/mammalian target of rapamycin
(mTOR) signaling pathway play an important role in diabetes mellitus (103, 104). Leptin activates ribosomal S6
kinase, an important physiological substrate of mTOR
kinase in the hypothalamus (92). The PI3K/Akt/mTOR
signaling pathway is required for an extremely diverse
array of cellular activities including proliferation and survival (105–107).
Leptin increases cell proliferation in mouse GT1-7 hypothalamic, C2C12 muscle, and AML12 liver cell lines
through mTOR and Akt signaling pathways (19). Moreover, in vitro and in vivo studies have suggested that leptin
stimulates cell proliferation through PI3K signaling in
myocytes (19, 108) and hepatocytes (109). Leptin may
also stimulate this pathway in human cancer cells (110,
111) and in human adipose (21), liver (112), and muscle
tissues (19, 113). Similar to the JAK2/STAT3 pathway, the
PI3K pathway is also important in central leptin action.
This pathway activates POMC-expressing neurons by activating ATP-sensitive potassium channels and voltagegated calcium channels (114). Also, similar to insulin, the
appetite-suppressing effects of leptin are attenuated by in-
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tracerebroventricular (icv) administration of PI3K inhibitors (116, 286). Interestingly, the insulin-PI3K pathway
hyperpolarizes POMC neurons, which makes them less
sensitive to leptin, and may be one common mechanism
for both leptin and insulin resistance in obesity (117, 118).
Chronic activation of the PI3K pathway in POMC neurons may cause leptin resistance and hyperphagia in mice
with POMC neuron-specific deletion of phosphatase and
tensin homolog (PTEN) (105). Hence, activation of the
PI3K signaling pathway in neuronal cells may influence
energy homeostasis and neuroendocrine function,
whereas activation of this pathway in the peripheral tissues may mediate leptin’s effect on insulin resistance.
D. Leptin and FoxO1 signaling
Forkhead box protein O1 (FoxO1) belongs to the forkhead family of transcription factors that are characterized
by a distinct forkhead domain (119) (Table 2 and Figure
1). The specific function of this transcription factor has not
yet been determined; however, it may contribute to myogenic growth and differentiation (119). FoxO1 is a downstream effector of insulin signaling with an important role
in the regulation of metabolism in various organs including liver (120), pancreas (121), muscle (122), adipose tissue (122), and hypothalamus (123). Also, FoxO1, as a
transcription factor, is one of the substrates for Akt phosphorylation resulting in cytoplasmic shuttling from the
nucleus, thereby inactivating FoxO1 (124, 125). FoxO1,
which stimulates the expression of AgRP and NPY and
inhibits POMC expression, is an important downstream
mediator of the PI3K pathway (286). It has been demonstrated that the activation of hypothalamic FoxO1 is inhibited by leptin via the PI3K pathway (123). In contrast,
overexpression of constitutively active FoxO1 in the
mediobasal hypothalamus of rats by adenoviral microinjection leads to a loss of the inhibitory effect of leptin
on feeding and results in body weight gain (126). Moreover, hypothalamus-specific FoxO1 knock-in mice
have increased food intake and decreased energy expenditure (127).
E. Leptin and SHP2/MAPK signaling
MAPKs are serine/threonine-specific protein kinases
that respond to extracellular stimuli (mitogens, osmotic
stress, heat-shock, and proinflammatory cytokines) and
regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis (19, 21, 128, 129). MAPKs encompass a
number of signaling molecules that include ERK1/2, p38
and c-Jun N-terminal kinase (JNK) (21). ERK1/2 represents the major MAPK involved in leptin’s central effects
Endocrine Reviews, June 2013, 34(3):377– 412
contributing to the regulation of food intake, energy expenditure, and body weight (3).
Leptin stimulates ERK1/2 activation via SH2-containing protein tyrosine phosphatase 2 (SHP2) (Table 2 and
Figure 1). SHP2 is a protein tyrosine phosphatase (PTP)
that contains 2 SH2 domains located in its NH2 terminus
as well as a COOH-terminal PTP domain (130). This specific structure suggests that SHP2 is involved in regulating
signals initiated by receptor tyrosine kinases (130). These
phosphotyrosines act as docking sites for recruitment of
SH2-containing proteins, including SHP2, to activate
downstream signaling cascades (131). SHP2 promotes
ERK1/2 activation in response to insulin and epidermal
growth factor binding to their receptors (132, 133).
Leptin induces phosphorylation of the Tyr985 amino
acid residue of the ObRb after JAK2 activation, thereby
creating a binding site for the carboxyl-terminal SH2 domain of SHP2 (134). SHP2 itself becomes phosphorylated,
recruits the adaptor protein growth factor receptor-bound
protein-2 and induces JAK2-dependent activation of
ERK1/2 (135). Leptin also activates the MAPK pathway
independently of SHP2, probably via receptor activation
leading to direct binding of growth factor receptor-bound
protein-2 to JAK2 (136). Recently, it has been shown that
young mice homozygous for a mutation at the site of the
leptin receptor phosphorylation were slightly leaner than
wild-type mice, although they still developed adult-onset
or DIO (137). These phenotypes probably do not reflect
the effect of this mutation on leptin-induced ERK activation but are consistent with the role of the mutation site as
a binding site for the suppressor of cytokine signaling 3
(SOCS3), which is a negative regulator of leptin receptor
signaling (137). In vitro studies have also demonstrated
that ERK is required for the phosphorylation of S6 by the
S6 kinase, which enhances cap-dependent translation and
protein synthesis (138).
Other members of the MAPK family, p38 and JNK, are
also activated by leptin in several cell types and present
mainly peripheral actions (139 –141), although the associated pathways have not been well characterized. In rat
cardiomyocytes, leptin administration stimulates p38,
which results in an increase in fatty acid oxidation,
whereas inhibition of p38 activation prevents
leptin-induced fatty acid oxidation (134). Similar to p38,
JNK is not activated in response to leptin treatment in
neuronal cells (135, 136) but confers an oncogenic potential to leptin’s action after its activation by promoting cancer cell survival and invasion (137).
F. Leptin and JAK2-independent signaling
You et al (137) observed that leptin may stimulate the
MAPK and STAT3 pathways in cultured cells that are
doi: 10.1210/er.2012-1053
genetically JAK2 deficient; however, the JAK2-independent signaling and its pathophysiological importance have
not been verified in animals or humans. The src tyrosine
kinase family members appear to be responsible for mediating leptin JAK2-independent signaling pathway
(138). The JAK2-dependent and independent signaling
pathways may synergistically mediate responses to leptin
(286). Because in vivo leptin actions may differ from in
vitro actions, studies of in vivo leptin signaling in humans
are needed to study the JAK2-independent leptin signaling
and implications.
IV. Leptin and Insulin Signaling
Insulin is a central hormone regulating carbohydrate and
fat metabolism in the body (142). Insulin causes cells in the
liver, muscle, and fat tissues to take up glucose from the
blood, storing it as glycogen in the liver and muscle (142–
144). Insulin binds to the extracellular portion of the
␣-subunits of the insulin receptor (143, 144). This, in turn,
causes a conformational change in the insulin receptor
that activates the kinase domain residing on the intracellular portion of the ␤-subunits (143, 144). The activated
kinase domain autophosphorylates tyrosine residues on
the C terminus of the receptor as well as tyrosine residues
in the insulin-receptor substrate (IRS)-1 protein (144). The
actions of insulin include 1) increasing or decreasing cellular intake of certain substances, most prominently increasing glucose uptake in muscle and adipose tissue (comprising about two-thirds of total body cells) (142, 144), 2)
increasing DNA replication and protein synthesis via control of amino acid uptake (145), and 3) modification of the
activity of numerous enzymes (146).
Evidence from in vivo and in vitro studies supports the
hypothesis that leptin and insulin signaling networks may
overlap on several levels. Intravenous infusion of leptin in
mice has several effects on insulin-regulated processes, including increased glucose turnover, increased glucose uptake in skeletal muscle and brown adipose tissue, and decreased hepatic glycogen content (147–149). In vivo leptin
administration has also been reported to stimulate insulin’s inhibitory effects on hepatic glucose output, while
antagonizing insulin’s effect on glucokinase and phosphoenolpyruvate carboxykinase (PEPCK) expression, 2
key metabolic enzymes (150 –152). In HepG2 human hepatoma cells, leptin has been shown to antagonize insulininduced down-regulation of PEPCK expression, decrease
insulin-stimulated tyrosine phosphorylation of IRS-1, and
enhance IRS-1-associated PI3K activity (153). Also, in
C2C12 muscle cells, leptin stimulates a non-IRS-1–associated PI3K and mimics insulin action on glucose trans-
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port and glycogen synthesis. In contrast, in OB-RL-transfected HepG2 cells, leptin treatment resulted in the
recruitment of p85 to IRS-2 but did not modulate the response to insulin (154). Interestingly, in Fao cells, leptin
alone had no effects on the insulin signaling pathway, but
leptin pretreatment transiently enhanced insulin-induced
tyrosine phosphorylation and PI3K binding to IRS-1,
while inhibiting these effects on IRS-2 (155). Also, this
study demonstrated that treatment by leptin alone induces
serine phosphorylation of Akt and glycogen synthase kinase 3 but to a lesser extent than treatment by insulin
alone, and that the combination of these hormones did not
result in an additive effect (155). These observations suggest complex interactions between the leptin and insulin
signaling pathways that can potentially lead to differential
modification of the metabolic and mitotic effects of insulin
exerted through IRS-1 and IRS-2 and the downstream kinases that are activated. Together, these data point toward
cell- and/or tissue-specific interactions between leptin and
insulin signaling that are quite diverse and complex. Although the details of this interaction remain to be elucidated, we propose that leptin may contribute to some of
the alterations in the metabolic and mitotic effects of
insulin action that are involved in the development
of insulin resistance, a characteristic manifestation of
type 2 diabetes.
An example of the overlap between leptin and insulin
resistance has been reported elsewhere (156). The JAK2/
STAT3 pathway leads to increased transcription and expression of SOCS3. In fact, SOCS3 acts as a feedback
inhibitor by attenuating ObR signaling, thereby playing a
key role in leptin resistance, whereas it also attenuates
insulin signaling, thereby playing a key role in insulin resistance (157). Apart from leptin, SOCS3 may be induced
by other adipocytokines, including resistin (158), TNF-␣
(159), and IL-6 (160), which may act as amplifiers of
SOCS3 expression, thereby further increasing both leptin
resistance and insulin resistance.
In summary, it has been shown that a complex network
of interacting signaling pathways appears to regulate food
intake, energy balance, and body weight (161), suggesting
that, in addition to signaling in the CNS, leptin exerts its
metabolic effects by acting directly in peripheral tissues.
The relative importance of this signaling for regulating
adiposity and glucose homeostasis in the periphery remains to be explored. Furthermore, other important challenges include 1) the identification of different signaling
pathways downstream of leptin that are integrated in the
regulation of body weight, 2) the leptin-insulin cross talk
in the CNS, 3) the elucidation of the molecular pathways
responsible for leptin resistance/tolerance in obesity, and
4) the elucidation of the underlying mechanisms respon-
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sible for the overlapping leptin and insulin resistance occurring in the brain in pathological states such as obesity
and diabetes that are associated with insulin resistance in
the periphery.
V. Leptin Resistance or Tolerance
The poor efficacy of endogenous leptin to induce weight
reduction in obese individuals has given rise to the term of
functional leptin resistance, which is based on the concept
of insulin resistance in diabetes type 2, where reduced cellular and metabolic insulin responsiveness coexist with
insulin hypersecretion. The lack of a precise definition of
the term leptin resistance in a universal and quantifiable
manner led the National Institutes of Health to conduct a
workshop, Toward a Clinical Definition of Leptin Resistance (162). Leptin resistance or, as in our opinion is more
correctly stated as tolerance, could be generally defined as
the failure of endogenous or exogenous leptin to promote
anticipated salutary metabolic outcomes, such as suppression of appetite and weight gain and stimulation of energy
expenditure, although leptin’s inability to induce desired
responses in specific situations results from multiple molecular, neural, environmental, and behavioral mechanisms (162).
The main physiological cause for leptin hypersecretion
is diet-induced expansion of adipocytes. However, in
DIO, the physiological function of progressive hyperleptinemia remains to be fully defined. It has been shown,
however, that lipotoxicity in nonadipose tissues of congenitally aleptinemic obese rodents is far greater than in
hyperleptinemic DIO rodents, leading to ectopic lipid deposition in liver, pancreatic islets, and heart and skeletal
Table 3.
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muscle and causing severe organ dysfunction and cell
death with a disease cluster similar to metabolic syndrome
(52, 163, 164). Increasing leptin levels in this condition
appear to prevent lipotoxicity by minimizing ectopic lipid
accumulation into nonadipocytes via leptin-induced fatty
acid oxidation. In obesity, an expanding adipose compartment may initially improve whole-body insulin sensitivity,
at least temporarily (165, 166). However, later in life, as
energy storage capacity in adipocytes is exceeded during
the period between the onset of overweight/obesity and
the start of the metabolic syndrome, which is considered
to be the result of failure to prevent organ damage inflicted
by ectopic fatty acids and metabolic trauma (163, 167),
leptin resistance develops.
The onset of leptin resistance varies among ObRbexpressing neurons. Diet-induced leptin resistance appears
to manifest first in the ARC of the hypothalamus and later
in other hypothalamic areas such as the VMH and dorsomedial hypothalamus (153). Interestingly, the impairment in the ObRb/PI3K signaling pathway precedes that
of the ObRb/JAK2/STAT3 pathway (154).
First, leptin resistance was thought to be due to leptin
receptor mutations or mutations of other genes downstream of leptin, such as POMC and MC4R, which also
produce an obese phenotype with associated neuroendocrine dysfunction (3). The instance of genetic mutation
abrogating leptin receptor function is similar to classical
hormone resistance/insensitivity syndromes (type A insulin resistance, GH insensitivity, etc,), in which genetic alterations of the hormone receptor prevent hormone action. Nonetheless, only a few cases of obesity in humans
are due to monogenic syndromes; instead, most cases are
multifactorial (155). Hence, the underlying mechanisms
Potential Mechanisms of Underlying Leptin Resistance or Tolerance
Leptin Resistance or Tolerance
Gene mutations
Impaired leptin signaling
Impaired leptin neural circuitry
Impaired BBB transport
Impaired ObRb trafficking
ER stress
Saturable nature of leptin pathways
Leptin receptor
Molecules downstream of leptin receptor (POMC, MC4R)
SH2B1 2
SOCS3, PTP1B, SHP2 1
Altered synaptic plasticity
Axon guidance
ObRe–ObRa Antagonism
Triglycerides 1
Bardet-Biedl syndrome protein 2
UPR response 3 impaired STAT3 phosphorylation
At a free leptin level ⱖ40 –50 ng/ml
Leptin resistance occurs rarely due to monogenic mutations of leptin receptor or other genes downstream of leptin (POMC and MC4R). Leptin tolerance is usually
multifactorial due to 1) impaired activation (down-regulation of SH2B1) or inhibition (up-regulation of SOCS3 or PTP1B) of leptin signaling; 2) impaired leptin-induced
neural plasticity/circuitry, given that defects in MC4R and BDNF receptor signaling in the hypothalamus may modulate synaptic plasticity and axon guidance; 3)
impaired leptin transport across the BBB because soluble leptin receptor isoform (ObRe) may antagonize the action of ObRa (which is abundantly expressed in brain
microvessels constituting the BBB), thereby resulting in leptin’s endocytosis, whereas hypertriglyceridemia may also impair leptin transport; 4) impaired ObRb trafficking,
as has been reported in relation to Bardet-Biedl syndrome proteins (responsible for promoting ObRb trafficking to the plasma membrane) impairment; 5) ER stress,
which promotes the UPR, thereby inhibiting STAT3 phosphorylation; and 6) saturable nature of leptin signaling pathways.
doi: 10.1210/er.2012-1053
responsible for leptin resistance are apparently multiple
and probably include the following (Table 3): 1) impaired leptin receptor signaling (11, 127, 156 –161,
163–167), 2) defective leptin transport across the BBB
(168 –172), 3) impaired ObRb trafficking (173, 174), 4)
endoplasmic reticulum (ER) stress (21, 175–177), 5)
saturable nature of leptin signaling pathways (19, 20,
178, 179), and 6) impaired leptin-induced neural plasticity/circuitry (180 –183).
A. Impaired activation of leptin receptor signaling/
inhibitors of leptin signaling
Leptin signaling is controlled by both positive (SH2B
adaptor protein 1, SH2B1) and negative (SOCS3 and
PTP1B) regulators. SH2B1 is an SH2 and pleckstrin homology domain-containing adaptor implicated in cell signal transduction and represents an important positive regulator of leptin sensitivity (115). SH2B1 binds to Tyr813
and enhances JAK2 stimulation, promoting leptin signaling pathways downstream of JAK2 (111). Moreover,
SH2B1 binds directly to IRS-1 and IRS-2, inhibiting tyrosine dephosphorylation of IRS-1/2 and increasing PI3K
pathway activation (115).
A large contributor to leptin resistance is the defect in
negative feedback mechanisms such as SOCS3 and
PTP1B, which dampen leptin receptor signaling and prevent overactivation of leptin signaling pathways (168,
169) (Figure 1). The JAK/STAT pathway is negatively regulated by members of the SOCS family, and leptin signaling via Tyr1138 and STAT3 induces SOCS3 expression
(169, 170), which in turn switches off leptin signaling by
binding to tyrosine residue Tyr985 and inhibiting phosphorylation/activation of JAK2 (171). Therefore, SOCS3
represents a pivotal feedback mechanism preventing the
overactivation of leptin-signaling pathways. Overexpression of SOCS3 has been proposed as one of the main mechanisms for the onset of leptin resistance (169). Indeed,
hypothalamic SOCS3 expression is significantly increased
in several leptin-resistant animal models (169). Immunohistochemical studies suggest that the ARC is selectively
leptin resistant in DIO mice, and this may be caused by
elevated SOCS3 in this hypothalamic nucleus (172). Mutation of Tyr985 to leucine (l/l) increases leptin sensitivity
in female mice (173). However, in contrast to female l/l
mice, both male and female Tyr985 mice showed increased
susceptibility to high-fat diet (HFD)-induced obesity, supporting a positive action of signaling via Tyr985 in attenuating diet-induced impairment of energy metabolism.
Also, because PTP1B is increased in leptin-resistant animals, a role for PTP1B in the onset of leptin resistance has
been suggested (174). PTP1B is a ubiquitously expressed
tyrosine phosphatase implicated in the negative regulation
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of leptin and insulin receptor signaling (156, 157, 163)
(Figure 1). It has been shown that PTP1B deficiency in
LepRb-expressing neurons results in reduced body weight
and adiposity compared with wild-type controls and likely
underlies the improved metabolic phenotype of global and
brain-specific PTP1B-deficient models, suggesting that
PTP1B may, independent of leptin signaling, contribute to
the regulation of energy balance in mice (184). PTP1B
represents another signaling molecule that may inhibit leptin signaling via JAK2 dephosphorylation (164). PTP1Bknockout mice are lean and have increased leptin sensitivity (164). Overexpression of the endogenous leptin
enhancer SH2B1 has been shown to counteract PTP1Bmediated inhibition of leptin signaling in cultured cells
(175). PTP1B expression is increased by HFD feeding and
inflammation (176), but it is still unclear how PTP1B expression and activity are regulated after leptin stimulation
or in case of DIO.
SHP2 has also recently been shown to play a critical role
in leptin signaling by functioning in the hypothalamic control of energy balance and metabolism (177) (Table 2 and
Figure 1). SHP2 appears to down-regulate the ObRbJAK2/STAT3 pathway while promoting ERK1/2 activation by leptin (177, 178). It has been shown that a prominent phenotype of the mutant (CaMKII␣-Cre:Shp2flox/
flox or CaSKO) mice was the development of early-onset
obesity, with increased serum levels of leptin, insulin, glucose, and triglycerides (178). This study demonstrated
that SHP2 down-regulates JAK2/STAT3 activation by
leptin in the hypothalamus but that JAK2/STAT3 downregulation is offset by the dominant SHP2 promotion of
the leptin-stimulated ERK1/2 pathway, leading to induction rather than suppression of leptin resistance upon
SHP2 deletion in the brain. These results suggest that a
primary function of SHP2 in postmitotic forebrain neurons is to control energy balance and metabolism, representing a critical signaling component of leptin receptor
ObRb in the hypothalamus (178). Hence, pharmaceutical
augmentation of SHP2 activity in the brain might prove to
be an efficient therapeutic strategy for alleviation of leptin
resistance in obese patients.
B. Impaired leptin transport across the BBB
Leptin enters the brain by a saturable transport system
(179). To reach the ObRb-expressing neurons in the brain,
leptin has to cross the BBB (180). Leptin levels in the cerebrospinal fluid are decreased in cases of obesity, suggesting that defective leptin transport may contribute to
leptin resistance (180). The short isoform of the leptin
receptor, ObRa, abundantly expressed in brain microvessels constituting the BBB, plays a key role in leptin transport across the BBB (181). The soluble leptin receptor
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isoform ObRe has been shown to antagonize ObRa action
and leptin transport through inhibition of leptin surface
binding and endocytosis (171). However, a distinct subpopulation of ARC neurons, which can be labeled by BBBimpermeable fluorescent tracers, has been shown to respond more rapidly and sensitively to circulating leptin
compared with other hypothalamic ObRb neurons. These
neurons might therefore make direct contact with the
blood circulation by projections through the BBB (179,
180). In addition to hyperleptinemia, hypertriglyceridemia may also impair leptin transport (171). The exact
clinical significance of these findings and/or any differential effects of icv leptin administration in humans remain
to be elucidated.
Further studies are needed to clarify the contribution of
impaired leptin transport to the pathogenesis of leptin resistance. Because leptin does not appear to be able to cross
the BBB easily, it may be possible to develop leptin agonists
that cross the BBB more freely or, possibly, antagonists
acting only peripherally. Such agents could possibly have
beneficial effects on immune responses in autoimmune
disease and/or on cardiovascular disease, without causing
excess weight gain as would be expected from blocking
central leptin action (182).
C. Impaired ObRb trafficking
Few ObRbs are located on the plasma membrane mediating leptin effects; most ObRbs are present in the transGolgi network and in small vesicles (173). It has been
shown that specific proteins, named Bardet-Biedl syndrome proteins, are responsible in promoting ObRb trafficking to the plasma membrane (173). In mouse models,
deletion of Bardet-Biedl syndrome proteins results in leptin resistance and obesity (174). Nonetheless, the importance of these proteins in humans with obesity has not
been determined yet.
D. ER stress
ER homeostasis is regulated by balancing ER loading of
nascent proteins with ER ability to fold these proteins. An
imbalance may result in an overload of unfolded/misfolded proteins in the ER lumen, inducing ER stress (175).
ER stress promotes the unfolded protein response (UPR)
involving the activation of several UPR intracellular signaling pathways (176).
ER stress has recently been shown to play a role in the
development of leptin resistance. Obese, diabetic humans
and animals present higher levels of ER stress in the liver,
adipose tissue, and pancreatic ␤-cells (175), suggesting
that ER capacity is directly related to leptin sensitivity
(183, 184). Hence, ER stress reversal via treatment with
chemical chaperones that decrease ER stress (176) could
Endocrine Reviews, June 2013, 34(3):377– 412
be a strategy to sensitize obese mice, and by extension
humans, to leptin. Studies have shown that reducing ER
function in mice creates ER stress, leading to blocked leptin action and hence leptin resistance, with a significant
augmentation of obesity on a HFD (183). This suggests
that ER stress inhibits STAT3 phosphorylation at an upstream step and provides a potential mechanism by which
increased ER stress antagonizes STAT3-mediated leptin
signaling. We have demonstrated that pretreatment with
the ER stress inducers, tunicamycin and dithiothreitol,
completely blocks leptin-stimulated STAT3 activation in
human primary adipocytes and human peripheral blood
mononuclear cells (PBMCs) in vitro, suggesting that increased ER stress in obese people may induce leptin resistance (21). ER stress may also act via other pathways. For
example, overnutrition atypically activates the inhibitor
of nuclear factor ␬B (NF-␬B) kinase subunit ␤ (IKK␤)/
NF-␬B, at least in part through elevated ER stress in the
hypothalamus (185). Although forced activation of hypothalamic IKK␤/NF-␬B interrupts central leptin signaling
and actions, suppression of IKK␤ significantly protects
against obesity and leptin resistance (185). Because in vivo
leptin actions may differ from in vitro actions, studies of
in vivo leptin signaling in humans are needed to explore
this hypothesis. Also, the cross talk between leptin and
UPR signaling pathways needs to be fully clarified.
E. Saturable nature of leptin signaling pathways
To study leptin signaling in humans, we have recently
performed for the first time in vivo experiments involving
metreleptin administration in humans in doses that result
in an increase of circulating levels of free leptin up to a peak
level of 40 to 50 ng/mL (20). In long-term leptin administration trials in humans, we found that circulating free
leptin levels did not result in weight loss, which indicates
that free leptin levels in or above the ⬃40- to 50-ng/mL
range may be clinically ineffective (20). Also, we observed
that in vivo metreleptin administration (0.01 mg/kg for 30
minutes) induces phospho-STAT3 in both hAT and hPBMCs, but this signaling is saturable at a level of ⬃50 ng/mL
metreleptin (20). These levels are higher than the putative
threshold for saturating the BBB leptin transport system,
which may explain the absence of clinical effect of high
leptin levels in obese humans despite the dramatic effects
seen when replacing leptin in subjects with very low concentrations of leptin (178, 179).
Consistent with this result, we have also observed in
hAT ex vivo and human primary adipocytes in vitro and
in mouse hypothalamic, muscle, and liver cell lines in vitro
that leptin signaling pathways were saturable at a level of
⬃50 ng/mL (19), suggesting that no additional signaling
effect may be observed at higher doses. Overall, we suggest
doi: 10.1210/er.2012-1053
that the saturable nature of leptin signaling pathways may
play a key role in the development of leptin tolerance in
obese humans.
F. Impaired leptin neural circuitry
It has been shown that leptin-deficient (ob/ob) mice
differ from wild-type mice in terms of numbers of excitatory and inhibitory synapses and in terms of postsynaptic
currents onto NPY and POMC neurons (181). Hence,
when leptin was delivered systemically to ob/ob mice, the
synaptic density rapidly normalized, an effect detectable
within 6 hours, several hours before leptin’s effect on food
intake (181). This study suggested that leptin-mediated
plasticity in the ob/ob hypothalamus may underlie some of
the hormone’s behavioral effects. Also, it has been reported that leptin changes brain structure, neuron excitability, and synaptic plasticity and regulates feeding circuits, suggesting that leptin may play a role in the
development of the CNS (182). Indeed, leptin has been
proposed to be a crucial regulator of both synaptic plasticity and axon guidance within the hypothalamus, suggesting fresh links between nutrition and neurodevelopment mediated by leptin, with potentially important
implications for the physiology of energy balance and
body weight homeostasis (183). Leptin’s anorexigenic and
metabolic effects are mediated by a sophisticated network
of neurons in the hypothalamus as well as other areas in
the brain. Leptin resistance, hyperphagia and obesity are
characteristic manifestations after defects in MC4R and
BDNF receptor signaling in the paraventricular hypothalamus and the VMH, respectively (180). Therefore, leptin
sensitivity may be impaired by genetic or environmental
factors that modulate leptin neural circuitry. More studies
are required to study in depth the leptin neurocircuity by
analyzing its anatomic, biochemical, and electrical
components.
VI. Effects of Leptin on Glucose Metabolism in
Animals and Humans
Leptin replacement is a promising therapeutic approach in
several disease states characterized by aleptinemia or hypoleptinemia, including congenital complete leptin deficiency, and states of energy deprivation, comprising
anorexia nervosa or milder forms of hypothalamic amenorrhea, as well as syndromes of insulin resistance observed
in conditions such as congenital or acquired lipodystrophy. Conversely, states of energy excess such as gardenvariety obesity and diabetes type 2, which represent the
vast majority of the obese and diabetic population, are
associated with hyperleptinemia and are characterized by
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the absence of clinical effects of leptin, reflecting leptin
tolerance or leptin resistance. Table 4 displays leptin administration effects in different disease states based on
initial leptinemia. If the leptin resistance or tolerance obstacle is overcome, leptin treatment would become an effective therapeutic approach against common obesity and
diabetes type 2.
A. States of leptin deficiency
1. Congenital leptin deficiency
Mice homozygous for a nonsense mutation in the ob
gene, the ob/ob mice, have been studied for a long time and
represent a commonly used model of obesity. The first
demonstration of an effect of leptin on glucose homeostasis was reported in 1995 when these mice were treated
with ip injections of leptin (2, 5, 6). Administration of
leptin effectively decreased serum glucose and insulin concentrations in a dose-dependent manner, even at the lowest dose where no significant body weight loss was observed. Similarly, a single icv injection of leptin improved
glucose tolerance as assessed by an ip glucose tolerance test
(GTT) (186). In contrast, db/db mice, which have a mutation in the leptin receptor gene resulting in expression of
a truncated and dysfunctional receptor, show no reduction in body weight or improvement in metabolic abnormalities in response to treatment with leptin (187). These
observations collectively suggest that leptin may play an
important role in glucose metabolism and that leptin
administration may correct the metabolic disturbance
in leptin-deficient states.
Congenital leptin deficiency is a rare autosomal recessive disorder, caused by mutations in the gene encoding for
leptin. In 1997, 2 severely obese children who were members of the same highly consanguineous pedigree of Pakistani origin were reported to exhibit nearly undetectable
concentrations of serum leptin (188). They had a homozygous frame-shift mutation involving the deletion of a single nucleotide in codon 133 of the leptin gene. Clinically,
they exhibited profound obesity, hyperphagia, hyperinsulinemia, and hyperlipidemia as well as reproductive and
immune dysfunction (189 –191). Leptin replacement in 1
of these congenital leptin-deficient children decreased appetite, food intake, body weight, and serum insulin and
cholesterol concentrations (192), and similar effects have
been noted with leptin replacement in other unrelated individuals with leptin deficiency (193, 194). Since then,
several other Pakistani children with leptin deficiency
have been identified (195). We have studied another group
of 4 adult patients of Turkish origin who carry a homozygous missense mutation (78, 191, 196, 197). Hyperinsulinemia was a common feature in these patients, and 1 of
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Table 4.
Baselinea
Effects of Leptin on Glucose Metabolism
Endocrine Reviews, June 2013, 34(3):377– 412
Effects of Leptin Administration in Different Disease State on the Basis of Circulating Leptin Levels at
Disease States Associated With Different Initial Leptin
Levels
Therapeutic Approach
Main Results
Disease states associated with undetectable initial leptin levels
(⬍0.05 ng/mL)
Congenital leptin deficiency
Leptin
Significantly reduced food intake and body weight
and improved metabolic derangements
Disease states associated with very low initial leptinemia
(⬍5 ng/mL)
Congenital lipodystrophy syndromes
Leptin
Significantly improved insulin sensitivity and
dyslipidemia
Significantly decreased central fat mass and
improved insulin sensitivity but not dyslipidemia
Recuperation of menstruation; correction in the
gonadal, thyroid, GH, and adrenal axes;
improvements in bone metabolism and skeletal
health
Improved insulin sensitivity, glycemic control, and
dyslipidemia in 2 patients
HALS
Leptin
HA
Leptin
Diabetes mellitus type 1
Leptin and reduced insulin
Disease states associated with moderately low initial
leptinemia (⬃5 ng/mL)
Lipodystrophy-associated diabetes type 2
Leptin
Ameliorated lipidemic profile but not glucose
abnormalities
Disease states associated with initial hyperleptinemia
(⬎15 ng/mL)
Garden-variety obesity
Leptin monotherapy
No effect on weight reduction and glycemic
control
Moderately diminished body weight
Did not alter body weight, marginal or no
amelioration in glycemic control
Garden-variety obesity
Obesity and diabetes type 2
a
Leptin and pramlintide
Leptin
Adapted from Refs. 3, 4, 10, and 11.
them had diabetes mellitus (196). Leptin replacement dramatically reduced body weight and food intake in all patients. Leptin effectively decreased fasting and postprandial glycemia and normalized glycated hemoglobin
(HbA1C) levels within 2 months of treatment in the diabetic patient (191). The other patients, who had normal
glucose and insulin levels at baseline, maintained normal
fasting glucose levels, but their insulin and C-peptide levels
decreased significantly to less than half of their baseline
values (191). Among them, only 1 adult male patient was
submitted to meal tolerance tests before and after 1 week,
18 months, and 24 months of leptin replacement (198).
The authors used deconvolution analysis of C-peptide kinetics, modified insulin kinetics modeling, and minimal
glucose modeling to determine pancreatic insulin secretion, hepatic insulin extraction, and peripheral insulin sensitivity. After 1 week, leptin replacement increased hepatic
insulin extraction by 2.4-fold (resulting in a 1.8-fold decrease of posthepatic insulin delivery), without significant
changes in insulin secretion, and also increased insulin
sensitivity by 10%. After 24 months, leptin replacement
increased insulin sensitivity by at least 10-fold, with additional decreases in insulin secretion and hepatic insulin
extraction (198).
In 1998, Clément et al (199) reported a homozygous
mutation in the human leptin receptor gene that results in
a truncated leptin receptor lacking both the transmembrane and the intracellular domains. Patients homozygous
for this mutation showed early-onset morbid obesity,
whereas their serum leptin concentrations were much
higher than normal. These patients presented normal fasting glycemia and normal glucose tolerance despite their
extreme obesity (199). More recently, Farooqi et al (200)
sequenced the leptin receptor gene from subjects with
early, severe obesity to determine the prevalence of pathologic mutations. Of the 300 subjects, 8 (3%) had nonsense
or missense leptin receptor gene mutations; 7 were homozygous and 1 was heterozygous. Most subjects with the
mutation presented normal glucose concentrations, although the 2 oldest adults had type 2 diabetes managed
with oral hypoglycemic medications. All subjects had hyperinsulinemia to a degree consistent with their obesity
(200). These data demonstrate that, in humans, several
phenotypic features seen in subjects with leptin receptor
mutations are not as severe as those in subjects with leptin
deficiency. This is different from the situation observed in
mice, where mice homozygous for a mutation in the leptin
receptor gene (the db/db mouse) develop more evident dia-
doi: 10.1210/er.2012-1053
betes than obesity when compared with ob/ob mice (201).
The discrepancy between humans and mice is not yet explained, although mouse studies have shown that genetic
background is an important modifier of the effects of leptin
deficiency on insulin resistance and diabetes (202).
Leptin is currently available for life-long treatment of
subjects with congenital leptin deficiency through a manufacturer-sponsored expanded-access program (203,
204). Figure 2 depicts the effect of recombinant leptin
administration in congenital leptin deficiency.
2. Lipodystrophy
Lipodystrophy is a group of clinically heterogeneous
acquired or inherited disorders characterized by complete
or partial absence of sc fat (lipoatrophy) that can occur in
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conjunction with the pathological accumulation of adipose tissue (lipohypertrophy) in other distinct regions of
the body (10, 204). Although congenital lipodystrophies
are exceedingly rare, acquired lipodystrophies (especially
those associated with HIV infection and its treatment) are
more common. Interestingly, lipodystrophic patients exhibit insulin resistance, hyperglycemia, dyslipidemia, and
hepatic steatosis (205). The severity of these metabolic
derangements typically correlates with the degree of adipose tissue loss.
Several mouse models of lipodystrophy exist, and the
metabolic profiles of these models are similar to those of
human lipodystrophy (206). Among them, the lipodystrophic adipocyte fatty acid binding protein 2 sterol reg-
Figure 2.
Figure 2. The effect of recombinant leptin administration in leptin deficiency or leptin excess states. Recombinant leptin may have beneficial effects
when administered in leptin-deficiency states, but minimal benefit and/or mostly adverse effects when administered in leptin-excess states. In
congenital leptin deficiency and congenital lipodystrophy, recombinant leptin administration results in metabolic and neuroendocrine
improvement; improvement seems to be more limited in HIV-associated acquired lipodystrophy syndrome, in which coadministration of
pioglitazone, which acts by up-regulating endogenous adiponectin, may increase the metabolic benefit. On the other hand, recombinant leptin
administration in type 2 diabetes mellitus and/or common obesity and normal or high circulating leptin levels has minimal or null metabolic effect,
whereas it increases circulating leptin-binding protein and antileptin antibodies. Coadministration of pramlintide, an amylin analog targeting leptin
tolerance, or leptin administration after weight loss, when leptin’s declined levels increase appetite, might prove to be of some benefit. Similarly,
leptin up-regulation in animal models with NAFLD resulted in increased inflammation and fibrosis, thereby progression to NASH. Data on adverse
effects, including renal impairrment or T-cell lymphoma, observed mainly in a minority of leptin-deficiency patients, are currently inconclusive. Data
on carcinogenic effect of leptin, mainly observed in hyperleptinemic individuals, are also inconclusive but may be tissue-specific; however,
hypoleptinemia itself may be also implicated in carcinogenesis in hypoleptinemic individuals, and thus this aspect of leptin physiology remains to
be fully elucidated. *, Only experimental data.
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Effects of Leptin on Glucose Metabolism
ulatory element-binding protein 1c (aP2-SREBP-1c) transgenic mice exhibit many typical features of human
generalized lipodystrophy (207). These animals have
marked insulin resistance, hyperglycemia, and dyslipidemia and very low serum concentrations of leptin due to the
lack of sc adipose tissue. When these mice were treated
with leptin, their metabolic abnormalities and diabetic
phenotypes were almost normalized (207). Leptin treatment was associated with reduced food intake and weight
loss, but inducing weight loss by restricting access to food
did not lead to changes in insulin or glucose concentrations in transgenic mice, suggesting that the beneficial effects of leptin are separate from its effects on body weight
(207). The icv administration of leptin was as effective as
peripheral administration (208).
Another mouse model of lipodystrophy is the lipoatrophic A-ZIP/F-1 mouse model (209), which has a more
severe phenotype with almost complete lack of adipose
tissue, insulin resistance and diabetes, and low leptin levels. In this mouse model, administration of a high dose of
leptin (30 ␮g/d) led to only moderate improvements in
glucose and insulin concentrations (209). In contrast,
transgenic overexpression of leptin in these mice leads to
a lipoatrophic mouse model that has elevated leptin concentrations (LepTg/⫹:A-ZIPTg/⫹). These mice have significantly fewer metabolic abnormalities when compared
with the low-leptin A-ZIP/F-1 mice (210). The somewhat
discrepant findings may be related to the difference in the
achieved leptin concentrations with exogenous administration versus transgenic overexpression of leptin. In contrast to the former study in which plasma leptin concentration increased to 5 ng/mL (209), plasma leptin
concentrations in the latter study were markedly elevated
to 50 ng/mL (210). Collectively, these animal experiments
demonstrated that exogenous leptin administration may
overcome the diabetic abnormalities characteristic of lipodystrophy, and thus, these studies prompted therapeutic
trials of leptin replacement in patients with lipodystrophy.
In humans, congenital lipodystrophy syndromes are
rare; there have been fewer than 1000 described cases in
the literature (203, 211). Lipodystrophic subjects have
partial or total leptin deficiency (222). Leptin replacement
dramatically improves dyslipidemia and insulin sensitivity
and reduced HbA1C levels and intrahepatic fat content in
various types of human lipodystrophy, notably those associated with severe hypoleptinemia (fasting serum leptin
less than 4 –5 ng/mL in our laboratory) (213–216, 218 –
220, 319). Fasting blood glucose and HbA1C levels decreased markedly even in patients who are not fully responsive to other antihyperglycemic medications or high
doses of insulin. Javor et al (216) also reported that 15
patients with lipoatrophic diabetes were able to decrease
Endocrine Reviews, June 2013, 34(3):377– 412
or even discontinue diabetic therapy and maintain normoglycemia after 12 months of leptin replacement. Petersen et al (214) performed a hyperinsulinemic-euglycemic clamp in 3 patients with lipoatrophic diabetes and
showed remarkable improvement in insulin sensitivity after leptin treatment. This beneficial effect was seen both
with hepatic insulin sensitivity and with whole-body insulin sensitivity. In conjunction with this, there was an
86% reduction in intrahepatic triglyceride content and a
33% reduction in muscle triglyceride content (214).
Chong et al (218) recently published an open-label, uncontrolled prospective study in 48 patients with various
acquired and inherited forms of lipodystrophy. Leptin replacement effectively decreased serum triglyceride concentrations by 59% and HbA1C levels by 1.5 percentage
points within 1 year in these patients. The benefits of leptin
replacement were sustained for up to 8 years of follow-up
(218). Oral and Chan (220) collected several small, nonrandomized, open-label trials in a composite study reporting on a total of more than 100 patients with severe lipodystrophy. Based on these studies, they reported that
leptin treatment resulted in improvement in several metabolic parameters, including glycemic control, insulin sensitivity, plasma triglycerides, caloric intake, liver volume
and lipid content, and intramyocellular lipid content.
These beneficial responses were durable after 3 years of
therapy (221).
However, lipodystrophy comprises a heterogeneous
group of disorders with diverse circulating levels of leptin
(222). Indeed, most patients with lipodystrophy may exhibit moderate hypoleptinemia (fasting serum leptin ⬃5
ng/mL). Recent data have shown that although leptin
treatment is effective in ameliorating lipid profiles, notably hypertriglyceridemia, it does not restore metabolic homeostasis in lipodystrophic subjects with moderate hypoleptinemia (223), hence questioning the antidiabetic
potential of leptin in lipodystrophic patients. Therefore,
lipodystrophic subjects with moderate hypoleptinemia are
expected to respond poorly to leptin’s effect on glycemic
control but may benefit from its hypolipidemic effect. This
limitation of leptin treatment in the context of lipodystrophy associated with moderately low levels of circulating leptin highlights the need of developing better therapeutic approaches including combination therapy to treat
metabolic derangements in these patients.
Leptin administration in replacement doses constitutes
an important step forward in the understanding and treatment of various lipodystrophic syndromes, conditions
characterized by a hypoleptinemic state. Particularly, recombinant methionyl leptin administration in patients
with lipodystrophy exhibiting severe hypoleptinemia
ameliorated hyperinsulinemia, insulin resistance, hyper-
doi: 10.1210/er.2012-1053
glycemia, hypertriglyceridemia, and neuroendocrine abnormalities without significant adverse effects and provided the rationale for metreleptin treatment in these
patients. It is important to underscore that the antidiabetic
effect of leptin observed in these patients was achieved
even after discontinuation of previously administered antidiabetic treatment, therefore excluding the possibility of
a synergistic positive effect of antidiabetic medication and
leptin on glucose and lipid abnormalities (213). However,
there are several caveats. Existing studies are all open-label
and uncontrolled; hence, a placebo-controlled trial is warranted, although the small number of patients and the lack
of firm diagnostic criteria present hurdles to this endeavor
(203). Well-designed, probably crossover, randomized,
placebo-controlled trials would be needed to accurately
assess and quantify efficacy as well as to allow for a comparison with the current standard of care. Furthermore,
the side-effect profile of leptin has not yet been fully characterized. Deterioration of renal function, development of
lymphomas, and other side effects have been reported in
lipodystrophic subjects (223–225), but because these
studies were not placebo controlled, it remains unknown
whether the observed side effects are leptin-specific or random and/or represent the natural history of the underlying
disease. Thus, although the optimal treatment regimen for
this condition has not yet been fully determined, metreleptin is currently available for these subjects as part of an
expanded access program, while an application for approval for this indication is under review by the FDA.
Figure 2 depicts the effect of recombinant leptin administration in lipodystrophy.
3. HIV-associated lipodystrophy syndrome
Currently, the most prevalent type of lipodystrophy is
an acquired form of the syndrome that occurs in HIVinfected individuals treated with highly active antiretroviral therapy (HAART) (224). HIV-associated lipodystrophy syndrome (HALS) affects an estimated 15% to 36%
of HIV-infected patients and is associated with an increased risk of insulin resistance, diabetes mellitus, dyslipidemia, and cardiovascular disease (225). HALS has
been associated with dyslipidemia including elevated serum low-density lipoprotein (LDL) cholesterol and triglyceride (TG) levels and lower high-density lipoprotein
(HDL) cholesterol (226). HALS patients usually exhibit sc
fat loss and increased abdominal fat. The impact of lipodystrophy on the psychosocial health in HIV-positive individuals, ranging from somatic discomfort to low selfesteem, stigmatization, and depression can be significant
(227). The exact physiological mechanisms that lead to
HALS are still not fully defined, but it has been suggested
that protease inhibitors interfere with peroxisome prolif-
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393
erator-activated receptor-␥ (PPAR␥) action leading to an
impairment of normal metabolic processes in the adipocyte (228). Nucleoside analogs are also associated with
HALS, which is thought to be secondary to mitochondrial
injury. There may also be direct effects of the HIV itself
(224, 228).
In patients with HIV who are on HAART, leptin levels
are mostly related to their overall fat mass, as also seen in
individuals without HIV infection (229 –231). Adiponectin levels, which are also low in patients with HIV, are
mainly related to abnormal fat distribution rather than
overall fat mass (232). Approximately 20% to 30% of
individuals who have HALS manifest hypoadiponectinemia and hypoleptinemia, but these manifestations are less
dramatic than those seen in individuals with congenital
lipodystrophies (231). Nevertheless, both lower adiponectin and leptin levels have been associated with worse
insulin resistance (231). Hence, we and others have investigated the role of leptin replacement in these patients.
Nonetheless, generally it will be fair to expect a less dramatic response to leptin treatment in individuals suffering
from HALS given that these patients do not manifest an
absolute leptin deficiency comparable to congenital lipodystrophy (203).
In our initial randomized, placebo-controlled, crossover 2-month interventional study, we found that leptin in
physiological doses improved metabolic disturbances in
these patients (233). Leptin treatment was associated with
a 15% decrease in central fat mass as well as significant
improvements in insulin sensitivity and fasting insulin and
glucose levels, albeit having no effects on LDL and TG
(233). These results were confirmed by a longer independent study of open-label leptin treatment for 6 months
(234). Leptin treatment was associated with a 32% decrease in visceral fat as well as significant improvements in
fasting insulin, glucose levels, and lipid parameters including a decrease in LDL and non-HDL cholesterol and an
increase in HDL by the sixth month (234). This study
showed that whole-body insulin sensitivity was markedly
improved and found that the leptin-induced increase in
insulin sensitivity was especially pronounced in the liver
but not skeletal muscle (234). These observations suggest
that the benefits of leptin replacement are sustained, and
even increased, for as long as treatment continues in patients with HALS. Although there are no head to head
comparisons, studies performed to date indicate that leptin’s ability to improve insulin sensitivity is comparable to
or better than that of other available medications, including metformin and thiazolidinediones (235, 236). However, the more pronounced effect of leptin on lipid metabolism in the study by Mulligan et al (234) needs to be
interpreted cautiously given that this study was nonran-
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Effects of Leptin on Glucose Metabolism
domized and not placebo-controlled and its study participants continued to use their lipid-lowering regimens
during leptin treatment. Recent results from a small randomized, double-blinded, placebo-controlled clinical trial
indicate that leptin administration improves glycemia and
non-HDL cholesterol levels to some extent but cannot
ameliorate lipid kinetics in adults with HIV-associated
dyslipidemic lipodystrophy, providing a mechanistic reasoning behind the inconsistent effect of leptin on lipid profiles (237). Specifically, metreleptin administration to hypoleptinemic patients with HIV-associated dyslipidemic
lipodystrophy at doses that significantly elevate plasma
leptin levels does not ameliorate the markedly abnormal
fasting lipid kinetic defects characteristic of this condition,
ie, accelerated lipolysis and adipocyte and hepatic reesterification, with blunted oxidative disposal of free fatty
acids (237). Conversely, recombinant human GH and human GHRH, which present beneficial effects on lipid metabolism, have been shown to improve visceral fat, TG,
and cholesterol levels but not glucose parameters in patients with HALS, presenting also an unclear impact on
cardiovascular endpoint (238, 239).
Similar to leptin, hypoadiponectinemia is associated
with insulin resistance, hypertriglyceridemia, and adipose
tissue redistribution in patients with HALS (240 –242).
Adiponectin administration has been demonstrated in animals to improve insulin sensitivity and dyslipidemia (243,
244). Although adiponectin or leptin alone only partly
alleviate insulin resistance in mouse models of lipodystrophy, the combined administration of both hormones fully
normalizes insulin sensitivity (244). Given that no synthetic form of adiponectin is yet available for human use,
animal studies as well as studies on medications that indirectly increase endogenous levels of adiponectin such as
thiazolidinediones, have highlighted adiponectin’s therapeutic potential (245). We have found that pioglitazone, a
thiazolidinedione that increases adiponectin levels, may
have beneficial effects on HALS-associated insulin resistance. Recently, we performed a randomized, doubleblinded pilot study on the combined administration of
leptin and pioglitazone for 3 months in 9 HALS patients
(246). Compared with pioglitazone alone, combined
treatment reduced fasting serum insulin concentrations,
increased adiponectin concentrations, improved insulin
resistance (homeostasis model assessment [HOMA]), and
attenuated postprandial glycemia in response to a mixed
meal (246). These preliminary findings indicate that this
combination could further improve glycemic control and
needs to be replicated in larger and longer-term studies. If
confirmed and proven to be superior to the current standard of care, the treatment of HALS in the future may
involve leptin replacement in conjunction with pioglita-
Endocrine Reviews, June 2013, 34(3):377– 412
zone and/or adiponectin. Figure 2 depicts the effect of
recombinant leptin administration in HALS.
4. Hypothalamic amenorrhea
Hypothalamic amenorrhea (HA) is a disorder characterized by the cessation of menstrual cycles with anovulatory infertility and moderate to severe hypoleptinemia,
usually caused by reduced food intake or chronic energy
deficiency secondary to strenuous exercise (204). Leptin
administration to lean women who are affected by this
disorder and undertake strenuous exercise resulted in
recuperation of reproductive outcomes, correction in
the gonadal, thyroid, GH, and adrenal axes, and improvements in markers of bone formation (247–249).
Nonetheless, larger clinical trials are needed to confirm
the previous studies.
B. States of leptin excess
1. Common obese state
In contrast to the few obese subjects with congenital
leptin deficiency, most obese individuals exhibit greater
leptin concentrations than lean subjects due to their
greater amount of fat mass and are unresponsive to exogenous leptin in terms of anorectic effects, body weight
reduction, and glycemic control, due to leptin resistance as
discussed in Introduction (22, 23) (Table 5). These results
reduced expectations from leptin-based antiobesity therapeutic approaches.
Despite their shortcomings, mouse models with HFDinduced obesity may provide important insights into understanding the effects of leptin on glucose metabolism in
obese humans because these mouse models are the closest
to human obesity. Chronic infusion of leptin in C57BL/6J
mice on HFD did not improve the glucose response to
insulin during an insulin tolerance test, even though the
body weight of mice effectively decreased compared with
control mice (250). Moderate hyperleptinemia achieved
by adenovirus gene therapy somewhat improved glucose
tolerance in animals that had 4-fold greater leptin concentrations compared with control rats (251). Therefore,
serum concentrations of leptin may be an important factor
responsible for the restoration of aberrant glucose metabolism in HFD-induced obese animal models. Leptin administration in other mouse models of obesity has shown
mixed results. Harris et al (252) found that leptin treatment improved insulin resistance and hyperglycemia in
some strains of db/db mice, but the effects depended on sex
and mode of administration (chronic or bolus ip administration). Other authors found no benefits of leptin administration in db/db mice (5). Leptin treatment in a mouse model
doi: 10.1210/er.2012-1053
Table 5.
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Disease States Associated With Leptin Deficiency and Leptin Resistancea
Disease State
Fat loss associated with leptin deficiency
Congenital generalized lipoatrophy
Estimated Prevalence
Rare
HAART-induced lipoatrophy
15%–36% of HIV-infected patients
HA (functional)
3%– 8.5% in women aged 13– 44 y
Up to 69% of trained female athletes
Anorexia nervosa
1%–3% of college-age girls
Obesity as a manifestation of leptin deficiency
Complete congenital leptin deficiency
Heterozygous leptin deficiency
Obesity associated with leptin resistance (involving
leptin and molecular signaling pathways
downstream of the leptin receptor)
Leptin receptor gene mutation
a
395
Rare
ⱕ5%– 6% in obese subjects
Rare
Clinical Characteristics
Generalized fat wasting, impaired glucose tolerance,
insulin resistance or type 2 diabetes, dyslipidemia,
hepatic steatosis, acanthosis nigricans
Fat wasting of the face, arms, legs, and buttocks;
impaired glucose tolerance, insulin resistance, or
type 2 diabetes; hypertriglyceridemia, hepatic
steatosis
Strenuous exercise, psychogenic stress, energy
deficit, osteoporosis, neuroendocrine dysfunction
with decreased GnRH pulsatility and estradiol
levels, decreased thyroid and IGF-I levels, and
increased GH levels
Disturbed body image, severe restriction of food
intake, body weight loss, neuroendocrine
dysfunction
Hyperphagia, early-onset morbid obesity
hypogonadotropic hypogonadism, advanced bone
age, hyperinsulinemia and type 2 diabetes,
immune dysfunction
Garden-variety obesity with hypoleptinemia relative
to fat mass, normal neuroendocrine function
POMC mutations
Rare
Prohormone convertase deficiency
Rare
MC4R mutations
5%– 8% of childhood obesity
Melanin-concentrating hormone receptor-1
mutations
Neurotropin receptor tropomyosin-related kinase
B mutations
Rare
Mutations of other molecules downstream of
leptin receptor
Mechanism to be discovered
Rare
Phenotype similar to congenital leptin deficiency,
hyperphagia but less remarkable
hyperinsulinemia, hypogonadotropic
hypogonadism, mild growth retardation,
hypothalamic hypothyroidism, abnormal GH
secretion
Hyperphagia, early-onset obesity, ACTH deficiency
with adrenal insufficiency/crisis, lack of MSH
function at MC1Rs resulting in pale skin and red
hair
Hyperphagia, early-onset obesity, hypogonadotropic
hypogonadism, abnormal glucose homeostasis,
hypoinsulinemia, hypocortisolemia
Hyperphagia, early-onset obesity, increased fat and
lean body mass, increased linear growth and bone
density, severe hyperinsulinemia
Dysregulation of energy homeostasis with onset in
childhood
BDNF deficiency resulting in severe obesity,
hyperphagia, developmental delay, and cognitive
dysfunction
Obesity with onset in childhood
⬎90% of obese individuals
Garden-variety obesity
Rare
Adapted from Refs. 3, 4, 10, and 11.
of obesity that is deficient in brown adipose tissue resulted in
no improvement in glucose metabolism (253).
Subsequently, Heymsfield et al (22) conducted a randomized, double-blind, placebo-controlled trial to determine the relationship between increasing doses of exogenous leptin administration and weight loss in both lean
and obese humans. The results of this trial indicated that
daily administration of recombinant human methionyl
leptin induced dose-dependent but modest weight loss in
most but not all subjects. Only at pharmacological doses
did leptin induce some consistent degree of weight loss, but
even then, the effect was relatively mild (average weight
loss was 7.1 kg after 24 weeks in the group receiving the
highest dose of leptin). In addition, these investigators performed a standard oral GTT at baseline and after 24 weeks
and found no indication that leptin administration af-
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Effects of Leptin on Glucose Metabolism
fected glycemic control (22). Another study also demonstrated that weekly injection of 60 mg of pegylated recombinant human leptin did not lead to clinically
significant weight loss after 8 weeks of treatment, despite
serum leptin concentrations being as high as 3000 ng/mL,
ie, 100-fold higher than physiological levels. Insulin sensitivity, assessed with the HOMA score, was also not significantly affected by leptin treatment (254). This has been
confirmed in a recent study using the hyperinsulinemiceuglycemic clamp, where leptin treatment for 14 days did
not have any effect on insulin sensitivity (281). These results were confirmed by others and illustrate that leptin
administration is not an effective treatment for metabolic
disturbances in common obesity, at least not unless leptin
resistance can be overcome (256, 257). Nevertheless, in a
manner equivalent to administration of insulin for the
control of glycemia in type 2 diabetes with insulin resistance, the possibility exists that leptin administration
might be able to overcome leptin resistance.
In leptin-based antiobesity approaches, another important issue to consider is that leptin levels drop dramatically
with weight loss and remain low for up to 1 year after
weight loss (258 –260). This has been proposed to be associated with activation of mechanisms inducing weight
regain, such as increased food intake and reduced energy
expenditure (259) as seen in the case of lean subjects (261).
Hence, studies have looked at the role of leptin replacement to physiological levels after weight loss. Small studies
have shown an improvement in weight loss maintenance
as well as a reversal of changes in thyroid hormones, energy expenditure, and neural activity centers involved in
the regulatory, emotional, and cognitive control of food
intake (259, 262). However, the fact that these studies
were small and of sequential study design indicates that
future randomized and controlled studies are required to
define this potential use of leptin in more detail. This may
be related to saturability of the leptin pathways at higher
leptin concentrations, leading to absent response to increases beyond the saturation level but marked responses
after weight loss when leptin levels are low (20). In this
respect, studies of leptin administration in lean women
showed a further reduction in fat mass without a reduction
in lean body mass, indicating that lean subjects with low
physiological leptin levels at baseline are sensitive to
exogenously administered leptin, which decreases primarily fat mass while sparing lean mass and increasing
bone mass (12).
Recent clinical data have shown that combination
treatment with leptin and pramlintide, an amylin analog,
modestly decreased body weight (⫺12%) in leptin-resistant obese individuals more than leptin or amylin alone,
but the effect of the combination was rather additive not
Endocrine Reviews, June 2013, 34(3):377– 412
synergistic as had previously been suggested by experiments in rodents (264, 283). However, due to the relatively small period of treatment (20 weeks), it remains to
be seen whether a longer-term clinical trial would result in
further reduction or maintenance of body weight or may
cause unaticipated beneficial or adverse effects. To address these issues, longer-term clinical trials have been initiated, and results are awaited with interest.
In summary, leptin monotherapy is not an effective
therapeutic approach for obesity in most obese subjects
(representing ⬃90% of the obese population) with hyperleptinemia (circulating leptin levels above 15 ng/mL).
However, the efficacy of leptin monotherapy or combination therapy in obese subjects exhibiting hypoleptinemia or normoleptinemia remains unknown. Figure 2 depicts the effect of recombinant leptin administration in the
common obese state.
2. Diabetes mellitus
a. Type 1 diabetes mellitus. Many patients with type 1 dia-
betes have low levels of leptin (265), and this has also been
seen in animal models of type 1 diabetes mellitus (266). A
decrease in leptin secretion may be related to a reduced
adipose mass and reduced assimilation and storage of energy substrates in adipose tissue in insulin deficiency
(266).
Hence, several studies have examined the effects of leptin administration on glucose metabolism in insulin-deficient animal models of diabetes mellitus. Subcutaneous
infusion of leptin restored euglycemia and normalized peripheral insulin sensitivity in streptozotocin (STZ)-induced type 1 diabetic animals (267, 272). Central leptin
infusion also restored euglycemia in STZ-induced diabetic
animals (269 –271). Similar effects of leptin were also
demonstrated in other studies by using various animal
models of type 1 diabetes (58, 272–274). Pair-feeding
studies indicate that decreased food intake does not account by itself for the restoration of normoglycemia in
leptin-treated type 1 diabetic animals (273). These effects
of leptin were achieved through an insulinlike or insulinsensitizing but insulin-independent mechanism mediated
by the CNS (68). It has been suggested that leptin may act
via activating intracellular signaling pathways that overlap with those of insulin and/or by other mechanisms
(mainly suppression of glucagon) that remain to be fully
elucidated. Indeed, leptin monotherapy or combination
with low-dose insulin reversed the lethal catabolic state via
suppression of hyperglucagonemia in nonobese diabetic
mice with uncontrolled type 1 diabetes (58, 67). Moreover, leptin normalized HbA1C levels with far less glucose
variability compared with insulin monotherapy (58). This
recent promising work from the Unger laboratory (54, 55)
doi: 10.1210/er.2012-1053
suggests that leptin administration in humans may present
many advantages over insulin monotherapy for the treatment of diabetes type 1, characterized as a condition with
relative leptin deficiency. In humans, significant reductions in circulating leptin levels have been documented in
the newly diagnosed untreated human type 1 diabetic patients, suggesting that reduced leptin secretion might be a
common feature in insulin-deficient diabetes (265). Insulin deficiency in type 1 diabetes leads to a state of increased
lipolysis from adipocytes elevating circulating levels of
free fatty acids and ketonemia. These metabolic products
may reduce adipocyte’s ability to secrete leptin, which signals an energy deficit. In view of its beneficial effects in
animals, it has been suggested that leptin replacement
therapy may prove to be a useful adjunct therapy to restore
euglycemia in type 1 diabetes (277). Indeed, 1 year of leptin therapy was effective in improving glycemic control
and lipid profiles in 2 patients with type 1 diabetes and
acquired generalized lipodystrophy (276). In these individuals, leptin therapy improved insulin sensitivity, although insulin was not completely discontinued but was
significantly reduced (276). Leptin’s main therapeutic
benefits in patients with type 1 diabetes may include its
slow-acting glycemia-lowering effect preferred over the
fast-acting glycemia-lowering effect that can trigger hypoglycemic events, its antisteatotic and antilipotoxic action in peripheral tissues preferred over the steatosis promoted by insulin therapy that may cause cardiovascular
disease, its suppressive effect on glucagon that could reduce the need for insulin, and its ability to restore insulin
secretion in ␤-islets by reversing lipotoxicity (277). Nonetheless, larger clinical trials are needed to be performed to
determine leptin’s safety and efficacy in reducing insulin
requirements, hyperglycemia, glycemic fluctuations, and
dyslipidemia in subjects with diabetes type 1.
b. Type 2 diabetes mellitus. The use of leptin in type 2 dia-
betes has generated interest in view of the potential insulinindependent activation of intracellular pathways involved
in glucose metabolism. Hence, several studies have investigated the use of leptin in animal models of type 2 diabetes
mellitus, and more recently, we and others published human studies (in this Section). Despite results from several
animal studies demonstrating that leptin ameliorated insulin resistance, glycemic control, and lipid abnormalities
in mice with diabetes type 2, the results of 2 clinical trials
have shown that leptin treatment is largely ineffective in
improving insulin resistance and diabetes in obese subjects
with type 2 diabetes (20, 281). Given the fact that a nonnegligible proportion of subjects with diabetes type 2 are
not obese, it will be important to evaluate the antidiabetic
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effect of leptin in those subjects who exhibit normal or low
levels of leptin.
Toyoshima et al (278) investigated the use of leptin in
the MKR mouse, a diabetic mouse model with normal
leptin levels and defects in IGF-I and insulin receptor signaling. They found an improvement in diabetes that was
independent of the reduced food intake and was associated with reduced lipid stores in liver and muscle (278).
Similarly, Kusakabe et al (279) generated a mouse model
mimicking a combination of human type 1 and type 2
diabetes using low-dose STZ and HFD and examined the
effect of leptin treatment. These animals exhibited hyperglycemia and hyperleptinemia and only mildly elevated
serum insulin levels, suggestive of both insulin deficiency
and insulin resistance. After leptin infusion, food intake
and body weight decreased, glucose tolerance improved,
and serum insulin levels decreased during an ip GTT. Pair
feeding showed that the improved glycemic control was
independent of the reduction in food intake (279). Finally,
our group has investigated leptin therapy in a mouse
model deficient in brown fat, which is hyperleptinemic
and very sensitive to DIO (253). In these mice, treatment
with ip leptin was not associated with any changes in insulin or glucose concentrations (253).
Human studies have also evaluated the use of leptin in
obese diabetic patients. Recently, we conducted a doubleblinded, placebo-controlled, randomized clinical trial to
evaluate the effects of leptin in obese type 2 diabetic patients
(20). Seventy-one obese subjects with diet-controlled type 2
diabetes mellitus were recruited and randomized to receive
either metreleptin (20 mg/d) or placebo for 16 weeks. Metreleptin administration did not alter body weight or circulating inflammatory markers, but marginally reduced
HbA1C (8.01 ⫾ 0.93 to 7.96 ⫾ 1.12, P ⫽ .03) (20). Furthermore, we have found that levels of leptin-binding protein and antibodies against metreleptin increased in response to metreleptin treatment, limiting circulating free
leptin to ⬃50 ng/mL despite mean total leptin levels of
⬃1000 ng/mL in these subjects. Although these levels are
higher than the putative threshold for saturating the BBB
leptin transport system (280), circulating free leptin levels
did not correlate with weight loss, indicating clinical ineffectiveness of free leptin levels in the 40- to 50-ng/mL
range. Mittendorfer et al (281) also performed a study to
evaluate the effects of exogenous leptin in obese type 2
diabetic patients. They conducted a randomized, placebocontrolled trial in obese subjects with newly diagnosed
type 2 diabetes assigned to placebo or low-dose (30 mg/d)
or high-dose (80 mg/d) metreleptin for 14 days and performed a hyperinsulinemic-euglycemic clamp in conjunction with stable isotope-labeled tracer infusions to evaluate multiorgan insulin sensitivity before and after leptin
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Effects of Leptin on Glucose Metabolism
treatment. There were no significant differences between
groups in body weight and body composition. Insulin sensitivity of the liver (suppression of glucose production),
skeletal muscle (stimulation of glucose uptake), and adipose tissue (suppression of lipolysis) and basal substrate
kinetics were not affected by leptin treatment, even though
serum leptin concentrations increased 150-fold compared
with baseline in the high-dose group (281). This is very
different from leptin replacement in lipodystrophic patients, where the obtained leptin levels were near-physiological (214).
These findings provide more evidence of leptin resistance in the population of obese diabetic subjects. Because
most patients with type 2 diabetes are overweight/obese
and present hyperleptinemia with leptin resistance, leptin
treatment is considered ineffective (20, 281). Targeting the
molecular mechanisms of leptin resistance will be important in the treatment for obesity and diabetes type 2. For
instance, it has been suggested that the combination of
leptin treatment with leptin sensitizers could be a potentially feasible way to overcome leptin resistance. Amylin
has been suggested to be one such sensitizer on the basis of
animal experiments (282). Amylin may act with leptin to
induce fat-specific weight reduction (274), and the amylin
analog pramlintide has been used in conjunction with leptin in clinical trials presenting modest effects (277) and
potential safety concerns (276). In a phase II clinical trial,
the combination of an amylin analog and recombinant
leptin produced significantly more weight loss than either
treatment alone in obese and overweight subjects (283).
This effect was accompanied by trends for improved metabolic parameters such as total cholesterol (⫺9%), LDL
cholesterol (⫺8%), glycemia (⫺4 mg/dl), insulinemia
(⫺22%), and insulin resistance assessed by HOMA
(⫺25%) (283). However, these results seem to be additive
rather than synergistic, which suggests that amylin may
have independent effects on weight loss but does not likely
improve leptin sensitivity. We have recently shown that
leptin administration does not influence circulating amylin levels (284), and subsequently, we have performed signaling studies in human adipose tissue ex vivo and human
primary adipocytes and peripheral blood mononuclear
cells in vitro (21). We demonstrated that leptin and amylin
alone and in combination activate STAT3, AMPK, Akt,
and ERK1/2 signaling pathways (21). These data indicate
that leptin and amylin activate overlapping intracellular
signaling pathways in humans and have additive, but not
synergistic, effects (21).
However, leptin resistance or tolerance may or may not
represent an insurmountable obstacle regarding the antidiabetic actions of leptin. Leptin resistance could selectively affect leptin signaling pathways related to appetite
Endocrine Reviews, June 2013, 34(3):377– 412
and body weight reduction and not those related to glycemic control. Although the ObRb/JAK2/STAT3 pathway is important for leptin-mediated reduction of appetite
and body weight, it plays a minor role in leptin’s ability to
improve euglycemia (285). Moreover, pharmacological
inhibition of the hypothalamic PI3K signaling pathway
impairs the insulin-sensitizing effects of leptin (286). Research aiming at identifying molecular mechanisms and
medications that could up-regulate insulin-sensitizing signaling pathways downstream of leptin is awaited. Data
from rodents have also indicated that low doses of leptin
can ameliorate hyperglycemia without affecting food intake or body weight, underscoring that the pathways underlying the glucose-lowering actions of leptin are more
sensitive than the ones responsible for its weight-reducing
effects. Future clinical trials are needed to uncover the
clear antidiabetic action of leptin in nonobese patients
with diabetes type 2 who exhibit normo- or hypoleptinemia due to low adipose tissue mass in contrast to previous
studies examining obese patients with type 2 diabetes. Results of larger studies on combination treatments or the
development of specific leptin sensitizers that would enhance leptin’s efficacy are awaited with great interest. Figure 2 depicts the effect of recombinant leptin administration in type 2 diabetes.
3. Nonalcoholic fatty liver disease
Nonalcoholic fatty liver disease (NAFLD), which is
considered to be the hepatic manifestation of insulin resistance syndrome, has emerged as a significant public
health problem with worldwide distribution. The prevalence of NAFLD in the general population is 10% to 46%
in the United States and 6% to 35% in the rest of the
world, with a median of approximately 20% (287). The
incidence of NAFLD in both adults and children is rising,
in conjunction with the growing epidemics of obesity and
type 2 diabetes mellitus. The histologic spectrum of
NAFLD encompasses a wide spectrum of liver damage
ranging from nonalcoholic simple steatosis (SS) to nonalcoholic steatohepatitis (NASH) and NASH-related cirrhosis with its complications. SS progresses to NASH in about
15% to 30% and in cirrhosis in less than 5% of cases,
whereas NASH progresses to cirrhosis in 10% to 15% of
cases over 10 years and in 25% to 30% of cases in the
presence of advanced fibrosis (288).
As described in the section of leptin signaling (Section
III), under normal conditions, leptin suppresses hepatic
glucose production and de novo lipogenesis, whereas it
induces fatty acid oxidation in hepatocytes, thereby providing an antisteatotic and insulin-sensitizing effect. On
the other hand, hyperleptinemia has been proposed to play
a role in the pathogenesis of NAFLD (156, 289). There is
doi: 10.1210/er.2012-1053
evidence that leptin acts as a proinflammatory and profibrogenic cytokine, thereby affecting liver fibrosis, a key
feature of NASH. Xenobiotics-induced liver fibrosis was
extremely diminished in ob/ob mice and Zucker (fa/fa)
rats (290). Activated hepatic stellate cells (HSCs) express
ObRb and possibly other ObR isoforms, whose activation
leads to increased expression of proinflammatory and
proangiogenic cytokines and growth factors, such as angiopoietin-1 and vascular endothelial growth factor,
which affect hepatic inflammation and fibrosis (291).
Moreover, leptin was shown to up-regulate collagen ␣1 in
HSCs through the sequence p38 MAPK activation and
SREPB-1c down-regulation (292). Furthermore, leptin
may induce hepatic fibrogenesis by stimulating the production of tissue inhibitor of metalloproteinase-1 (293)
and repressing matrix metalloproteinase-1 gene expression (294) in activated HSCs. Both these processes are
mediated by the JAK/STAT and the JAK-mediated H2O2dependant MAPK pathways. Inflammatory, fibrogenic,
and proliferative leptin actions on HSCs may also be mediated via nicotinamide adenine dinucleotide phosphate
oxidase, which acts downstream of JAK activation, but
independently of STAT3; inhibition of nicotinamide adenine dinucleotide phosphate oxidase in HSCs resulted in
a reduction of leptin-mediated up-regulation of fibrogenic
markers (collagen ␣1 and ␣-smooth muscle actin) and of
inflammatory mediators (monocyte chemotactic protein-1 and macrophage inflammatory proteins 1 and 2)
and in a reduction of leptin-mediated HSC proliferation
(295). Additionally, leptin facilitates proliferation and
prevents apoptosis of HSCs (296), and it modulates all
features of the activated phenotype of HSCs in a profibrogenic manner (myofibroblastic phenotype) (297).
Once activated, HSCs contribute to further leptin expression (298), thereby possibly establishing a vicious
cycle (156).
Data regarding the role of leptin on hepatic fibrosis via
an effect on Kupffer or sinusoidal endothelial cells are
currently limited. Leptin may promote hepatic fibrogenesis through up-regulation of TGF-␤ and connective tissue
growth factor in isolated Kupffer cells; based on this finding, Kupffer cells-HSCs cross talk has been proposed for
hepatic fibrosis (299). Leptin has also been reported to
affect hepatic fibrosis through up-regulation of TGF-␤ in
sinusoidal endothelial cells (290).
More recently, an up-regulation of CD14 (an endotoxin receptor recognizing bacterial lipopolysaccharide)
in Kupffer cells was followed by hyperreactivity toward
low-dose lipopolysaccharide in HFD steatotic mice but
not in chow-fed control mice, which resulted in NASH
progression (300). When recombinant leptin was administered in chow-fed mice, an up-regulation of CD14 in
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399
Kupffer cell was similarly observed resulting in hyperreactivity toward lipopolysaccharide, thereby inducing hepatic inflammation and fibrosis without steatosis. On the
contrary, recombinant leptin administration to ob/ob
mice did not up-regulate CD14 or induce inflammation
and fibrosis, despite severe steatosis (300); these results
demonstrated that leptin deficiency, apparently due to
lack of its lipolytic effects, may lead to hepatic steatosis,
but it is protective toward the progression of SS to NASH,
whereas excess of this proinflammatory adipocytokine
may favor hepatic inflammation and fibrosis.
In line with the aforementioned data, it was previously
speculated that leptin under normal conditions may prevent liver steatosis, whereas its effect on quiescent HSCs
and Kupffer and sinusoidal cells is minimal. However,
prolonged hyperleptinemia, as observed in leptin tolerance states (ie, common obesity), may ultimately result in
overexpression of SOCS3 and in activation of HSCs and
Kupffer and sinusoidal cells. Overexpressed SOCS3 may
aggravate both leptin tolerance and insulin resistance in
hepatocytes and outweigh the primarily beneficial effect of
leptin on hepatocytes. Activated HSCs and Kupffer and
sinusoidal cells, which seem to display minimal or no leptin tolerance, may trigger the proinflammatory and profibrogenic cascade (156).
Although evidence for the inflammatory and fibrogenic
role of leptin in NAFLD from in vivo and animal models
is strong, relevant data from clinical studies in NAFLD
patients are based mainly on cross-sectional studies, which
cannot establish a causative relationship. Most authors
have reported higher leptin levels in NAFLD (301, 302) or
NASH (303, 304) patients than controls, in parallel with
higher insulin resistance. However, other authors have
reported similar leptin levels between NASH patients and
controls (305, 306). Regarding liver histology, some authors have also reported that leptin levels were positively
associated with hepatic fibrosis (303, 307, 308) or inflammation (303, 308). However, other authors reported no
association between serum leptin levels and hepatic fibrosis or inflammation (304, 306).
Soluble leptin receptor (sOB-R) has been reported to be
lower in the NAFLD patients than controls, as well as
negatively associated with circulating leptin in one study,
which might be attributed to counteracting sOB-R downregulation (301). However, other authors have reported
higher sOB-R levels in morbidly obese patients with diabetes, which are positively associated with the stage of
hepatic fibrosis (309), whereas others found no association of sOB-R levels with hepatic histology in children
with NAFLD (308). More studies are needed to elucidate
the interaction of leptin with its soluble receptor and its
role, if any, in the pathogenesis of NAFLD. The cross-
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sectional nature of the aforementioned clinical studies together with the heterogeneity within them render the
drawing of any conclusion risky. Larger studies with better characterized and/or homogenous populations and
carefully matched controls are of importance.
Prospective data regarding circulating leptin levels in
NAFLD are limited. In a 3-year prospective study with
paired biopsies, serum leptin levels were decreased more in
patients with stable or improved disease compared with
those with disease worsening; however, leptin could not
independently predict disease or fibrosis progression
(310). In a 7-year prospective study, leptin levels were
higher in patients with than without NAFLD at baseline;
however, leptin change was similar in those with disease
remission or sustaining disease (311). The limitation of
this study was its noninvasive nature (NAFLD was not
biopsy-proven). Further prospective studies with paired
biopsies and long-term follow-up are needed.
The effect of various therapeutic interventions on circulating leptin levels in patients with NAFLD are summarized in Table 6. Briefly, leptin levels remained essentially
unaffected after treatment with pioglitazone (312),
rosiglitazone (312), atorvastatin (313), ezetimibe (314),
cysteamine (315), and ursodeoxycholic acid with or
without vitamin E (316) but increased after short-term
melatonin treatment (317) or decreased equally after
metformin and lifestyle modifications or only lifestyle
modifications (57).
Importantly, no study to date has investigated or is
planned to investigate the effects of recombinant leptin
administration on NAFLD patients with normal or high
leptin levels. On the other hand, metreleptin administered
in 10 NAFLD patients (8 with NASH) with lipodystrophy
for a mean duration of 6.6 months resulted in improvement of hepatic steatosis and ballooning but not portal
inflammation or fibrosis (63). These results are similar to
Table 6. Effect of Various Therapeutic Interventions
on Circulating Leptin Levels in Patients With NAFLD
Circulating Leptin
Levels
Ref.
Intervention
Duration
317
275
315
Melatonin 10 mg/d
Rosiglitazone 4 mg /d
Enteric-coated cysteamine
600 –2000 mg/d
Ezetimibe 10 mg/d
Ursodeoxycholic acid 12–15
mg/kg/d ⫾ Vitamin E
800 IU/d
Atorvastatin 10 mg/d
Metformin 1700 mg/d ⫾
diet/exercise
Pioglitazone 30 mg/d
28 d
6 mo
6 mo
Increased
Unchanged
Unchanged
2y
2y
Unchanged
Unchanged
2y
6 mo
Unchanged
Decreased in either
group
Unchanged
314
316
313
57
312
Data are presented in publication date order.
1y
Endocrine Reviews, June 2013, 34(3):377– 412
Imajo et al (300) experimental model, indicating that recombinant leptin administration in NAFLD patients and
lipodistrophy may improve steatosis but not fibrosis. Furthermore, there are 2 ongoing clinical trials having as primary endpoint the effect of recombinant leptin administration in hepatic histology in NAFLD patients with low
leptin levels. In one of them (single-group, prospective,
open-label), metreleptin (0.1 mg/kg/d once a day sc) in 10
adult male patients with NASH and low circulating leptin
levels, but not lipodystrophy, was to be administered for
1 year (NCT00596934). In the other study, (single-group,
prospective, open-label), metreleptin (0.1 mg/kg/d once a
day sc) was planned to be administered for 1 year in 20
male or female patients with SS or NASH and lipodystrophy (NCT01679197).
Despite the lack of direct clinical evidence, leptin administration in NAFLD patients with hyperleptinemia
might have adverse effect on liver fibrosis, thereby possibly worsening the prognosis of liver disease. If the results
of the Imajo et al study (300) were translated into human
pathophysiology, they might have 2 main implications: 1)
leptin excess, which is usually observed in common forms
of obesity, may be contributing toward NASH progression and 2) recombinant leptin administration for severe
obesity may adversely affect the liver of obese individuals,
because it may promote proinflammatory responses,
whereas it has no lipolytic effects above a certain level due
to its permissive role in controlling obesity (20). Considering that the prevalence of NAFLD in obese individuals
is 50% to 95%, this becomes of crucial importance. Figure
2 depicts the effect of recombinant leptin administration in
NAFLD.
C. Benefits, potential adverse effects, and challenges in
relation to leptin replacement therapy
The benefits and potential adverse effects of recombinant leptin administration in leptin deficiency or leptin
excess states are summarized in Table 3. Generally, leptin
replacement therapy using an analog of leptin, metreleptin, also known as recombinant methionyl human leptin,
has been proven effective for the treatment of congenital
leptin deficiency, congenital and non-HIV–related acquired generalized lipodystrophy associated with severe
hypoleptinemia, and HA (219, 220).
Metreleptin offers metabolic benefits such as improvements in insulin sensitivity, glucose tolerance, fasting glucose, glycosylated hemoglobin, hypertrigyceridemia, and
liver function tests (219, 220). Patients with partial lipodystrophy, including those with PPAR␥ mutations (216),
also gain metabolic benefits from leptin administration. In
these subjects, leptin administration has been extensively
studied in the context of open-label clinical trials (221).
doi: 10.1210/er.2012-1053
HIV patients with HALS also exhibit significant improvements in their metabolic profile that are comparable to
other treatment options such as metformin and thiazolidinediones (234). Leptin replacement therapy provides
benefits beyond metabolic improvements: it ameliorates
glomerular injury in generalized lipodystrophy (223), it
has immunomodulatory effects in hypoleptinemic patients with severe lipodystrophy (222), it normalizes menstrual abnormalities in young women with lipodystrophy
and polycystic ovary syndrome (224), and it improves the
thyroid, GH, and adrenal axis abnormalities seen in
women with HA (224).
Although open-label trials have shown benefits of metreleptin use, larger, randomized, placebo-controlled clinical trials are needed to conclusively demonstrate its efficacy and safety, particularly because severe adverse effects
have been noted, including deterioration of renal function
and proteinuric nephropathy (224) and occurrence of Tcell lymphomas (223) in a small number of patients with
lipodystrophy. It is important to underscore that the openlabel nature of the study design did not allow the investigators to establish or refute a causal link between metreleptin treatment and reported adverse effects. Similar
adverse effects would not be entirely unexpected on the
basis of the natural history of the disease, particularly in
patients suffering from acquired lipodystrophy, which is
traditionally thought to be due to autoimmune factors.
Approximately 25% of cases with acquired generalized
lipodystrophy are caused by autoimmune disease such as
juvenile-onset dermatomyositis, rheumatoid arthritis, systemic lupus erythematosus, and Sjögren syndrome (219).
Given the immunomodulatory effect of metreleptin,
which clearly regulates the Th1/Th2 imbalance in leptindeficient individuals (224), large, crossover, randomized,
placebo-controlled clinical trials of sufficient duration are
needed to study efficacy and adverse effects more tightly.
Potential disadvantages of leptin therapy may include increased immune system function and inflammation and
the generation of neutralizing autoantibodies against exogenous leptin (115, 190, 212, 219). Moreover, it has
been reported that leptin accelerates autoimmune diabetes
in the nonobese diabetic mouse model of diabetes type 1,
probably by inducing proinflammatory cell responses
(217).
It remains unknown whether similar adverse effects in
response to leptin administration could potentially also be
observed in disease states accompanied by hyperleptinemia due to leptin resistance such as garden-variety obesity.
It also remains unknown whether similar side effects could
be seen in response to higher than normal leptin levels,
which are needed to effectively lower glycemia in conditions such as type 1 diabetes. In these conditions, potential
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side effects of leptin may become really prevalent due to
the increased prevalence of the underlying disease. Common adverse events seen particularly in combination treatment with pramlintide/metreleptin in obese subjects included nausea and injection site erythema and were mild
to moderate and decreasing over time (263). It has been
proposed that leptin could possibly cause hypertension,
impair endothelial function, promote platelet aggregation
leading to thrombosis, increase immune function, foster
inflammation and angiogenesis, and worsen diabetic complications and other concomitant diseases on the basis of
preclinical studies, but no such side effects have been seen
in the clinic (283). We have failed to observe effects in
hypertension (255, 283), angiogenesis (263), or inflammation (20). Although it cannot be excluded that prolonged administration of leptin may cause hypertension,
particularly in predisposed obese diabetic individuals in
contrast to obese hypotensive subjects who present with
leptin deficiency (255), we and others have not observed
such side effects in our trials (20, 268). Moreover, leptin’s
action in suppressing glucagon may place patients suffering from type 1 diabetes at increased risk for severe hypoglycemic episodes by impairing the counterregulatory
response necessary to restore glycemia (283). Until now,
these particular side effects have not been reported in leptin-deficient lipodystrophic or other patients treated with
replacement doses of leptin. Other probable adverse effects may theoretically include sleep disorders, an early
onset of puberty in children, and an increased risk of unplanned pregnancy, but again, they have not yet been observed in the clinic, whereas the potential teratogenic effects of leptin treatment need to be explored.
It is of paramount importance to discuss the potential
carcinogenic adverse effects of leptin administration in
patients with garden-variety obesity. It has been proposed
that leptin may exert neoplastic effects via 2 mechanisms.
First, leptin can act directly on cancer cells by stimulating
receptor-mediated signaling pathways leading to tumor
cell growth, migration, and invasion (193). Notably, this
activity of leptin is commonly reinforced through entangled cross talk with multiple oncogenes, cytokines, and
growth factors. Second, leptin may act indirectly by reducing tissue sensitivity to insulin, causing hyperinsulinemia and by regulating inflammatory responses with overproduction of cytokines such as IL-6, IL-12, and TNF-␣
(284) and influencing tumor angiogenesis, but we have not
observed such effects of leptin in vivo (285). Leptin has
also been proposed to play a role in hormone-dependent
malignancies, such as breast and endometrial cancers, by
activating the enzyme aromatase, an enzyme responsible
for the transformation of androgens to estrogens (81). Expression of leptin receptors has been reported in numerous
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Effects of Leptin on Glucose Metabolism
cancer cell types including breast, colon, prostate, and
thyroid (80). Leptin, through its receptor ObRb, may
modulate growth and proliferation of cancer cells via activation of various growth and survival signaling pathways including canonical (JAK2/STAT3, PI3K/Akt, and
MAPK/ERK1/2) and noncanonical (protein kinase C,
JNK, and p38 MAPK) signaling pathways (80). For example, leptin has been demonstrated in vitro to stimulate
JNK in human breast cancer cells in both a time- and a
dose-dependent manner, with greater phosphorylated
JNK levels after long-term exposure (80). In breast cancer,
JNK activation by leptin leads to an up-regulation of matrix metalloproteinase-2 activity, which promotes cancer
cell invasion (80). Leptin exerts proliferative and antiapoptotic effects on human colon cancer cells, which are mediated in part though JNK activation (80). It should be
noted, however, that most in vitro studies have used extremely high leptin levels.
However, in contrast to many in vitro studies, epidemiological studies report inconsistent associations between serum leptin levels and risk of several malignancies.
For example, in the case of colorectal cancer (CC), an
obesity-associated cancer, some prospective studies found
a positive association between serum leptin levels and CC
risk (291), whereas others did not show any relationship.
Moreover, some studies revealed that even hypoleptinemia was associated with CC risk, independently from BMI
(293). Our group, which has focused on adipokines and
cancer, has recently shown that hypoleptinemia, and not
hyperleptinemia, was linked to pancreatic cancer independently from BMI and weight loss, to B cell chronic lymphocytic leukemia, and to low-risk myelodysplastic syndrome after adjustment for BMI and other risk factors
(297) but these associations may reflect reverse causality.
In addition, increasing serum leptin levels did not appear
to increase substantially the risk of premenopausal breast
cancer in situ, invasive pre- and postmenopausal breast
cancer, endometrial cancer, prostate cancer, multiple myeloma, melanoma, and lung cancer (318 –321). Thus, the
possible association of leptin and malignancies in vitro
appears to be not supported by published studies in humans. A possible association with leptin needs to be studied further with larger prospective, longitudinal, and
mechanistic studies, which are needed to prove causality,
provide further insights into both the mechanisms underlying the actions of this hormone and its potential role in
cancer, and analyze its action in tumor progression if leptin is prescribed as an alternative or adjunct approach in
patients with diabetes and malignancies in the future.
In conclusion, future larger trials using metreleptin are
needed to systematically determine 1) the diagnostic criteria to be used as indicating hypoleptinemia and thus
Endocrine Reviews, June 2013, 34(3):377– 412
serve as inclusion criteria in ongoing and future trials, 2)
the appropriate initial metreleptin dose, 3) how high the
dose of metreleptin should be raised (based upon which
algorithm) for the best metabolic response to be achieved
or what dose would be needed to safely break through a
possible resistance to metreleptin in certain individuals, 4)
how patients on metreleptin should be monitored, and 5)
whether the concomitant use of other leptin-sensitizing
treatments could be useful therapeutic options in the treatment of obesity or to prevent metabolic adaptation induced by caloric restriction and to promote weight maintenance. Garden-variety obesity is a chronic disease with
currently limited successful long-term therapy options,
apart from bariatric surgery, which is both costly and
risky. Combination therapy for obesity represents an encouraging step forward in the pharmacologic armamentarium. Finally, large randomized leptin administration
studies are needed to obtain accurate information on potential adverse effects and long-term outcomes.
VII. Future Directions
Leptin is an adipocyte-secreted hormone that interacts
with several organs that are involved in the regulation of
energy homeostasis and metabolism. Although great
progress has been made in terms of understanding leptin’s
pathophysiological role, several fundamental questions,
particularly regarding the effects of leptin on glucose metabolism, still remain to be answered. Much progress has
been made with leptin treatment in patients with leptin
deficiency and lipodystrophy, and such treatment does
correct metabolic abnormalities. Results from these studies suggest that leptin could prove to be a potential antidiabetic agent in leptin-deficient states. However, formal
double-blinded placebo-controlled phase III clinical trials
are required to accurately determine placebo-subtracted
efficacy and to assess comparative efficacy in relation to
other effective therapies, and dose-finding studies are necessary to help guide appropriate treatment for these individuals. It is also unclear whether all patients with lipodystrophy would benefit from leptin therapy or whether
only those with the most profound leptin deficiency are
more likely to benefit. In contrast, the vast majority of
obese individuals are hyperleptinemic and resistant or tolerant to exogenous leptin. Therefore, it is questionable
whether leptin alone can be used to favorably modify glucose metabolism in garden-variety obesity and/or diabetes. Hence, findings from ongoing and upcoming studies
combining leptin with other antiobesity medications or
sensitizers will be of particular interest.
doi: 10.1210/er.2012-1053
edrv.endojournals.org
Acknowledgments
13.
Address correspondence and requests for reprints to: Christos S. Mantzoros, MD, DSc, Professor of Medicine, Harvard Medical School,
JP9B52A, 150 South Huntington Avenue, Boston, Massachusetts
02130. E-mail: [email protected].
The Mantzoros laboratory is supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants 58785, 79929, 81913,
and AG032030 and a VA Merit award (Grant 10684957). The Mantzoros Laboratory is also supported by a discretionary grant from Beth
Israel Deaconess Medical Center.
All authors contributed to writing the manuscript. All authors read
and approved the final manuscript.
Disclosure Summary: All authors state that there is no conflict of
interest related to this paper.
16.
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