Am J Physiol Endocrinol Metab 294: E817–E826, 2008.
First published March 11, 2008; doi:10.1152/ajpendo.00733.2007.
Review
Cross-talk between estrogen and leptin signaling in the hypothalamus
Qian Gao1 and Tamas L. Horvath1,2,3
1
Section of Comparative Medicine and Departments of 2Obstetrics, Gynecology and Reproductive Sciences
and 3Neurobiology, Yale University School of Medicine, New Haven, Connecticut
Submitted 21 November 2007; accepted in final form 3 March 2008
obesity; metabolism; signal transducer and activator of transcription 3
Leptin Levels Index the Status of Energy Stores
LEPTIN CLONED AS THE FUNCTIONAL PRODUCT of the obese
mutation, was initially characterized as an anti-obesity hormone (121). However, its role is more accurately described as
a “fat reporter” (feedback signal) (119); that is, leptin itself has
no, or limited direct effect on fat tissues, instead, its anti-obesity
effect requires functional “controllers” (neuronal and/or humoral),
the machineries directly responsible for reducing food intake
and increasing energy expenditure. Mature leptin is a 16-kDa
peptide hormone synthesized and secreted by white adipocytes,
the major energy pool in the body. Leptin levels in relation to
the amount of body fat serves as an index of body energy
storage and feeds back to the central nervous system (CNS) to
regulate energy homoestasis (68). Thus, energy homeostasis is
reached in animals and humans by a mechanism that defines
negative energy balance as its default state, unless a negative
feedback signal is available upon elevated fat stores, indexed
by increased leptin levels. When this feedback mechanism is
disrupted (70), the brain continuously “senses” a state of
negative energy balance, promotes feeding, and reduces energy
expenditure by default.
Obesity Simulates a State of Negative Energy Balance
Although obesity is a state in which a huge amount of excess
body energy (fat) is accumulated, the behavior and physiology
of obese individuals mirror those promoted during a state of
negative energy balance, including hyperphagia and low metabolic rates. Under normal conditions, brain regions involved
Address for reprint requests and other correspondence: Q. Gao, Yale Univ.
School of Medicine, New Haven, CT 06520 (e-mail: [email protected]).
http://www.ajpendo.org
in long-term energy balance, by definition, must sense the
amount of existing fuel in the body and use this knowledge to
adjust energy intake and expenditure. That is, energy homeostasis is maintained tightly by surveillance of and responses to alteration in body energy stores: a negative energy
balance promotes food intake and restricts energy expenditure,
and vice versa. However, body energy levels are not sensed via
circulating levels of fuel molecules (i.e., glucose or lipids)
under most circumstances but, as described above, via leptin,
which indexes the amount of energy (fat) in store. When leptin
levels in the circulation are high, neurons in the hypothalamus
and elsewhere in the brain interpret a high energy status, and
thus inhibit food intake and increase energy expenditure. However, when leptin signaling is disrupted, as in leptin resistance
or, in extreme cases, in leptin or leptin receptor deficiencies,
the energy homeostatic machineries recognize a state of extreme negative energy balance and initiate various behavioral
and physiological responses, regardless of actual body energy
(fat) stores. Animals and humans with leptin signaling disrupted are not only hyperphagic but also have extreme difficulty utilizing stored energy (Fig. 1).
Negative Energy Balance Is Associated with Infertility
A characteristic phenotype of negative energy balance is
hypothalamic hypogonadism (10, 58). This condition is reversible upon recovery of energy stores. This evolutionary adaptation allows an individual or species to survive when food is
scarce (112). It is particularly important to female reproduction; a critical fat mass, greater than 10%, is required for
ovulation to occur in women (45). Hypogonadotropic hypogonadism is also a common phenotype in obesity caused by
genetic deficiencies in leptin signaling (19). The fact that
0193-1849/08 $8.00 Copyright © 2008 the American Physiological Society
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Gao Q, Horvath TL. Cross-talk between estrogen and leptin signaling in the
hypothalamus. Am J Physiol Endocrinol Metab 294: E817–E826, 2008. First
published March 11, 2008; doi:10.1152/ajpendo.00733.2007.—Obesity, characterized by enhanced food intake (hyperphagia) and reduced energy expenditure that
results in the accumulation of body fat, is a major risk factor for various diseases,
including diabetes, cardiovascular disease, and cancer. In the United States, more
than half of adults are overweight, and this number continues to increase. The
adipocyte-secreted hormone leptin and its downstream signaling mediators play
crucial roles in the regulation of energy balance. Leptin decreases feeding while
increasing energy expenditure and permitting energy-intensive neuroendocrine
processes, such as reproduction. Thus, leptin also modulates the neuroendocrine
reproductive axis. The gonadal steroid hormone estrogen plays a central role in
the regulation of reproduction and also contributes to the regulation of energy
balance. Estrogen deficiency promotes feeding and weight gain, and estrogen
facilitates, and to some extent mimics, some actions of leptin. In this review, we
examine the functions of estrogen and leptin in the brain, with a focus on
mechanisms by which leptin and estrogen cooperate in the regulation of energy
homeostasis.
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reproductive dysfunction in ob/ob mice can be reversed by
leptin treatment indicates that developmental abnormalities in
brain structures involved in reproduction caused by leptin
deficiency are insufficient to interfere with normal leptin regulation of reproduction (22).
Similarly, leptin treatment restores gonadotropin-releasing
hormone (GnRH) and luteinizing hormone (LH) secretion and
pubertal development in leptin-deficient patients, confirming
its critical role in the hypothalamic control of reproduction in
humans (42). Leptin pulsatility is positively and strongly correlated with LH and estrogen levels in normal cycling women
(66), whereas the mean leptin levels and diurnal leptin rhythm
are impaired in women suffering from hypothalamic amenorrhea (61, 69). Leptin also restores reproductive function in
food-deprived animals and humans, even though their energy
stores are not necessarily improved. Leptin accelerates the
onset of sexual maturation in ad libitum-fed postnatal mice (1,
23). More recently, recombinant leptin was reported to increase
mean LH levels and LH pulse frequency as well as estrogen
levels. It improved reproduction in women with hypothalamic
amenorrhea (116). Leptin replacement also restores the pituitary-gonadal axis in lipodystrophic patients (79).
Leptin directly acts within the hypothalamus to stimulate
GnRH secretion in vivo in rats (114). These findings suggest
that leptin functions as an energy indicator required for
normal hypothalamic control of reproduction. When leptin
signaling is diminished, the brain switches off the GnRH
and LH cycles, resulting in hypogonadotropic hypogonadism and infertility.
Leptin Signaling: Central Role of STAT3
A single gene in both rodents and humans encodes leptin
receptors (LRs) (24, 29, 107), a gp130-like receptor family
member of class 1 cytokine receptors, which include the
receptors for ciliary neurotropic factor (CNTF), leukemia inAJP-Endocrinol Metab • VOL
hibitory factor (LIF), oncostatin M (OSM), interleukin-6 (IL6), and granulocyte colony-stimulating factor (G-CSF), etc.
These receptors mediate various biological processes through
JAK-STAT signaling (104, 107). Six variants of LRs have so
far been identified (Fig. 2A), which differ in the COOH
terminals of their proteins (26, 48, 108). Leptin receptor-b
(LRb), which possesses the longest intracellular domain, is
evolutionary conserved among species and solely mediates
energy homeostasis. The mice that lack only LRb exhibit a
phenotype indistinguishable from that of leptin and leptin
receptor deficiencies (25, 26, 30, 62, 107).
LRb is highly expressed in hypothalamic neurons associated
with feeding and metabolism (40). Leptin binding to LRb
activates the associated JAK2 tyrosine kinase and then activates
the STAT3, STAT5, phosphatidylinositol 3⬘-kinase (PI3K), and
MAPK pathways, among others (Fig. 2B) (51, 74). Among
these pathways, STAT3 is crucial, since abrogation of LRbSTAT3 signaling, neuronal STAT3, or STAT3 in LRb neurons
recapitulates the obesity of db/db animals, including hyperphagia and decreased energy expernditure, to a great degree (6, 46,
84). During leptin signaling, JAK2 phosphorylates LRb on
three sites in its intracellular domain: Tyr985, Tyr1077, and
Tyr1138. Phosphorylated Tyr1138 (pY1138) recruits STAT3 to
the LRb-JAK2 complex (5, 7, 117), where JAK2 phosphorylates it (pY705). The subsequent dimerization and nuclear
transport of STAT3 result in the alteration of cell transcription
and function (94). For example, STAT3 directly activates
proopiomelanocortin (POMC) transcription to promote anorexia and increase energy expenditure.
Phosphorylation of Tyr985 (Y985) of the LRb recruits the
SH2 domain containing tyrosine phosphatase-2 (SHP-2) along
with the growth factor-bound protein-2 (GRB2) (9), which is
crucial for the activation of the MAPK pathway. The suppressor of cytokine signaling-3 (SOCS3), the STAT3 pathway-
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Fig. 1. Obesity is a state of negative energy
balance. Body energy levels are detected by
hypothalamic neurons through measuring of leptin levels in circulation. When leptin levels are
low, due to either food depletion or leptin signaling deficiency (ob/ob), the inhibition of leptin
to hypothalamic feeding and metabolic circuits
is released, and the default activity of these
systems promotes feeding and restricts energy
expenditure.
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CROSS-TALK BETWEEN ESTROGEN AND LEPTIN
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induced feedback inhibitor (101), competes with SHP-2 for
Y985. SOCS3 is involved in region-specific leptin resistance in
diet-induced obese mice (72), and deficiencies of it in the brain
suppress diet-induced obesity (71), as does mutation of Tyr985
of LRb (11). These observations suggest that Tyr985 of LRb
and SOCS3 contributes to feedback inhibition of leptin action
in vivo.
Less is known about the function of Tyr1077 of LRb and
STAT5 activation in leptin action. Nevertheless, leptin stimulation of STAT5 phosphorylation and nuclear accumulation in
the hypothalamus have recently been reported (51, 73). Furthermore, deletion of STAT5 in the brain results in obesity,
although the extent to which this reflects a defect in leptin
action remains unclear (63).
Although leptin activates the PI3K pathway in the brain, the
molecular details of this regulation remain enigmatic (77, 120).
Insulin receptor substrate-2 (IRS-2) may represent one intermediary, as CNS deletion of IRS-2 results in increased adiposity due to hyperphagia with decreased energy expenditure (16,
106, 118). The PI3K pathway also regulates the electrophysiology of hypothalamic neurons (102) and the function of the
sympathetic nervous system, which contribute to the reduction
of feeding (87).
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Estrogen Is a Potent Regulator of Both Energy Balance
and Fertility
Like leptin, the gonadal steroid hormone estrogen reduces
food intake and body adiposity and increases energy expenditure in animals and humans of both sexes through a hypothalamic mechanism (17, 35, 81). It exerts a profound impact on
reproduction both peripherally and centrally. The central effect
of estrogen in the regulation of reproduction is directly related
to reproductive hormone cycles. In fact, the actions of estrogen
on the hypothalamic GnRH neuronal network are required to
trigger the episodic release of GnRH that leads to a pulsatile
pattern of LH secretion (54) (Fig. 3). The ability of leptin to
restore fertility is also achieved by restoring GnRH and LH
surges, which in turn, reverse hypogonadotropic hypogonadism. In adult females, circulating estrogen is mainly produced
in the ovary. Locally, estrogen can be converted from testosterone and androstenedione by the enzyme cytochrome P-450
aromatase (P450aro). The levels of P450aro in male brains are
slightly higher than in females (64, 67, 92); however, aromatase-deficient mice accumulate excess adipose tissue in both
sexes (57) and impair male fertility (56, 89). In humans,
aromatase deficiency has been associated with hypogonado-
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Fig. 2. Leptin receptor-b (LRb) signaling is mediated
by STAT3. A: 6 splice variants of LRs, LRa–f, have
been identified. The long-form LRb activates STAT3
and is fully responsible for the leptin-regulated phenotype. B: at least 3 signal pathways, JAK-STAT, PI3K,
and MAPK, are activated upon leptin binding of LRb.
The JAK-STAT3 pathway appears to be dominant. Both
PI3K and MAPK are modestly involved in energy
homeostasis and may interact with STAT3 to regulate
homeostasis. See text for definitions.
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tropic hypogonadism and infertility in both sexes (14, 99),
suggesting that local estrogen is important for homeostasis and
reproduction. Consistent with this, P450aro is highly and
selectively expressed in the regions associated with metabolism, i.e., ventromedial hypothalamus (VMH) and reproduction, i.e., preoptic area (POA) (76).
Estrogen and Leptin Target Common Neuronal Structures
The primary sites of estrogen receptors (ERs) include the
same areas where LRs are located (82). In fact, estrogen and
leptin receptors are colocalized in neurons within the areas
known to coordinate metabolism and gonadal function, such as
the arcuate nucleus (ARC), VMH, and POA (34) (Fig. 4A).
Physical or chemical lesions to these regions (15, 109, 111)
result in hyperphagia and obesity, whereas expression of leptin
in these regions reduces food intake and body weight (4).
Similarly, estrogen infusions into the VMH, ARC, or paraventricular nucleus (PVN) reduce food intake and body weight
(17, 81). The ARC, VMH, and PVN form the hypothalamic
anorectic center, from which the “antiobesity” effect emanates
in response to leptin stimulation (95). In the ARC, for example,
the anorexogenic POMC neurons (Fig. 4B) act to inhibit food
intake through the release of the POMC cleavage product
␣-melanocyte-stimulating hormone (␣-MSH). The orexigenic
neuropeptide Y (NPY) neurons act against POMC neurons to
promote feeding; interestingly, these neurons are also implicated in fertility (41, 93). When leptin signaling is diminished,
POMC expression is reduced and NPY expression is increased.
Thus, leptin exerts its antiobesity effect by both activating
POMC neurons and inhibiting NPY neurons, while estrogen
exhibits similar molecular and cellular effects as leptin in these
regions.
Reproduction, on the other hand, is coordinated by the
hypothalamic anteroventral periventricular nucleus (AVPV)
and the POA, where GnRH neurons reside (50, 98) (Fig. 4).
GnRH neurons are the final output of a network that integrates
environmental and hormonal cues to regulate the secretion of
reproductive hormones; they are inhibited by negative energy
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Fig. 4. Common hypothalamic nuclei targeted by estrogen and leptin.
A: metabolic nuclei, the arcuate nucleus (ARC) and the ventromedial hypothalamic area (VMH), as well as the reproductive nuclei, the anteroventral
periventricular nucleus (AVPV) and the preoptic area (POA), where the GnRH
neurons reside, are located ventromedially in the brain. The top 2 panels are
coronal sections of mouse hypothalamus; bottom panel is a sagital section of
a mouse brain detailing the anterioposteral relationship between the POA and
ARC (yellow), both which are targeted by estrogen and leptin to control energy
balance and reproduction. B: proopiomelanocortin (POMC) neurons in the
ARC: GFP-labeled POMC neurons of the ARC are encircled by the white line,
whereas neuropeptide Y (NPY) neurons tend to localize within more medial
portion of the ARC (circled in yellow), with a significant degree of overlap
between the 2 populations. ME, median eminence; V3, 3rd ventricle.
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Fig. 3. Estrogen regulates the hypothalamic reproductive endocrine. Levels of
estrogen have both inhibitory and stimulatory effects on gonadotropin-releasing hormone (GnRH) expression and secretion. In normal cycling animals, low
levels of estrogen gently inhibit GnRH expression and secretion. Reducing
estrogen levels, as in ovariectomized (boxed area) animals, results in an
increase of GnRH expression and secretion. However, high levels of estrogen,
together with circadian cue, trigger GnRH surge. The pulsatile parameters of
GnRH secretion are based on findings in the ewe [adapted from Herbison (54)].
balance (37). Both inhibitory and stimulatory actions of estrogen on GnRH neurons during the cycle are required for
establishing a coordinated hormone cycle through distinct
pathways (20). The stimulatory effect of estrogen triggers the
episodic release of GnRH and induces a pulsatile pattern of LH
secretion (54). In rats, the GnRH neurons located in the rostral
POA were particularly important in triggering a GnRH surge.
The GnRH network requires preexposure to elevated estrogen
and the presence of a circadian input to initiate a cascade of
neural events (65, 115). The nature of these events remains to
be addressed. The induction of progesterone receptors in the
AVPV by estrogen (65) and the synaptic plasticity on GnRH
neurons may be involved (59, 103). Similarly, leptin also
affects the POA and GnRH neurons, albeit indirectly, as GnRH
neurons do not express LRb (114). Leptin pretreatment prevents fasting-induced reduction of the activities of GnRH
neurons (103), suggesting that the knowledge on preexisting of
body energy stores, indexed by leptin levels, is crucial for
GnRH neuron function. Thus, although estrogen and leptin
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each have some distinct actions via some neural populations
that respond to one but not the other, leptin and estrogen act in
many overlapping hypothalamic regions and neuron populations to regulate energy homeostasis and reproduction.
Estrogen Mimics Leptin’s Effect on Rewiring
of Melanocortin Neurons
Estrogen and Leptin Signaling Interact Via STAT3
The overlap in function and targeted nuclei between estrogen and leptin are overwhelming. However, whether this im-
Fig. 5. Estrogen (E2) receptors (ERs) activate
STAT3 to promote gene expression in the hypothalamus. Agonist-bound ERs activate STAT3
(tyrosine phosphorylation) independently of LRbmediated mechanism by direct binding or via
other signal transduction pathways such as
MAPK, PI3K, and Src kinase (Src-K). Activated
STAT3 alters gene transcription cellular function in corresponding hypothalamic neurons.
LRb-mediated STAT3 activation is not illustrated here (see Fig. 2).
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The hypothalamus senses peripheral signals to coordinate
body homeostasis through the neuroendocrine axis, and by
connecting to various brain structures. Estrogen and leptin both
act in overlapping neurons in the hypothalamus to regulate
long-term energy balance and fertility. How the two signals are
translated to appropriate neuronal adaptations to exert their
antiobesity effect is not well addressed. It has recently been
uncovered that leptin rapidly rewires the synaptic input on
hypothalamic melanocortin neurons, resulting in an increased
POMC tone (83) followed by decreased food intake and
adiposity. Estrogen also reduces appetite and adiposity (35,
112) and influences synaptology in unidentified cells in the
ARC (75). This suggests that synaptic plasticity may be a
common regulatory element of estrogen and leptin. Indeed, we
found that, like leptin, estrogen triggers robust increases in the
number of excitatory inputs on the ARC POMC neurons (47).
This leads to a corresponding change in the electronic tone in
these cells, measured as an increase in the events of random
presynaptic release. Interestingly and informatively, estrogen’s
effect on energy regulation is effective in leptin and LR mutant
mice. Consistent with this observation, that estrogen triggered
synaptic rewiring on POMC neurons is evident in ob/ob and
db/db mutant mice. Thus, estrogen and leptin signals in regulating energy homeostasis are, in part, translated to the synaptic
adaptations in the POMC neurons to induce an antiobese
neuronal response. Since both signals are also important for
normal reproduction, a similar mechanism underlying hypothalamic control of fertility may be expected.
plies a direct interaction between the two signals remains to be
addressed. At the least, this notion is supported in several
ways. First, estrogen sensitizes leptin signaling, whereas estrogen deficiency causes central leptin insensitivity and increased
hypothalamic NPY (2). For example, in females, chronic
estrogen withdrawal, as in ovariectomy in rodents and postmenopause in humans, causes leptin resistance, whereas estrogen replacement prevents this phenotype (2). More directly,
estrogen increases leptin-induced STAT3 phosphorylation in
the ARC (28), indicating that estrogen may interact with the
leptin pathway at the level of STAT3. Since estrogen’s effect
on homeostasis and synaptogenesis is independent of leptin
and LRs (35, 52), this suggests that interaction between estrogen and leptin signaling must bypass LRs and directly target
the leptin downstream component.
STAT3 as a target of estrogen signaling in cells has been
reported (12, 97). Distinct activation mechanisms by which
estrogen activates STAT3 have been observed (Fig. 5), which
may explain divergent effects of estrogen on STAT3 function
(positive or negative) in transcription. These mechanisms provide “shortcut” pathways bypassing membrane-associated receptors. For example, STAT3 is phosphorylated and activated
in response to estrogen in cells involving multiple intracellular
signal pathways that include MAPK, Src kinase, and PI3K (12,
18) and/or direct physical association between ERs and STAT3
(27). In the animals, it was observed that estrogen activates
STAT3 in the hypothalamus in a signal-transducing fashion.
Peripheral (ip) administrations of estrogen induced tyrosine
phosphorylation of STAT3 in the hypothalamus in less than 30
min. This effect of estrogen on STAT3 tyrosine phosphorylation is JAK independent but may involve the Src kinase
pathway (Ref. 47 and Nie Y, unpublished data), and is effective in obese mutant, e.g., db/db, mice. This is consistent with
the fact that estrogen reduces food intake and body weight. It
also regulates synaptology in hypothalamic melanocortin feeding circuits in wild-type, ob/ob, and db/db mutant mice. Finally, with a neural STAT3 knockout (STAT3N⫺/⫺) mouse
model, which exhibits obesity and infertility, a phenotype
highly resembling leptin deficiency (46), estrogen exhibited no
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effect on reducing body weight. These observations strongly
suggest that STAT3 proteins are positioned downstream of
estrogen signaling in neurons and are required for estrogen’s
antiobesity effect.
STAT3 in Reproduction and Metabolism
ER(s) Involved in Cross-Talk with STAT3
The cross-talk between estrogen and STAT3 is done, at least
in part, through classic ERs, the ligand-dependent nuclear
transcription factors, which sensitively respond to 17␤-estradiol. The potential roles for recently uncovered membrane ERs
(86) in this matter may not be ruled out; however, they require
more studies. The agonist-bound ER␣ and ER␤ activate STAT3 to
stimulate a STAT-regulated promoter in cells. This correlates
with cytoplasmic sublocalization of ERs and is independent of
DNA-binding domains of ERs, suggesting a nongenomic
mechanism of ERs (12, 97). Other interactive mechanisms
between ERs and STAT3 include direct physical coupling
between the two. For example, in the human neuroblastoma
cell line SK-N-BE, ER␣ blocks the mitogenic effect of TGF-␣
signaling and induces differentiation independently of ER␣’s
DNA binding activity but requires a transcriptionally active
STAT3. In this process, ER␣ directly binds to STAT3 (27). It
is also true that ERs and STAT3 are both known to be able to
associate coregulators, such as CREB, CBP/P300, and NcoA/
SRC1a (38, 90). Thus, the interaction between ERs and STAT3
may involve coregulators. The binding between ERs and
STAT3 in general does not alter the binding specificity of
STAT3 to DNA and does not involve estrogen response elements. Finally, STAT3 also enhances the transactivation function of ERs (33, 21), suggesting that ERs and STAT3 may act
mutually as coactivators to facilitate signaling.
Consistent with these in vitro data, ER␣ has been suggested
as the main ER that mediates estrogen’s antiobesity effect in
both sexes (49, 91). When knocked out, it causes obesity and
infertility in both males and females (55, 53). ER␣-null animals develop obesity with a more than 100% increase of their
fat tissue compared with controls, whereas ER␤-null mice are
lean. In the ARC, ER␣ is the dominant ER, and levels of ER␤
are negligible (80). Notably, levels of circulating estrogen in
obese ER␣-null animals are 10 times higher than those in their
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Questions to Be Assessed
From signal cross-talk between gonadal hormone estrogen
and adipo-hormone leptin point of view, several key questions
remain to be assessed:
Where do estrogen and leptin signaling meet? Whether
STAT3 activation by estrogen occurs in LRb-expressing neurons, and if so, which subpopulation(s) of those neurons in the
hypothalamus may be involved has not yet been assessed.
Since ER␣ is found only in a subset of LRb-expressing neurons
in the hypothalamic nuclei associated with feeding and metabolism, and estrogen’s effect on homeostasis is less potent than
leptin, it is possible that estrogen only activates STAT3 in a
subset of leptin-sensitive neurons in the hypothalamus. Similarly, estrogen may activate STAT3 in non-LRb neurons as
well. This question is also related to the issue of whether
estrogen signaling-STAT3 interaction is indeed occurring in
the same cells, which is supported by cell culture studies, or
whether it is a secondary effect.
How do ERs trigger STAT3 phosphorylation in cells? Even
if estrogen signaling and STAT3 directly interact (as acute
phosphorylation of STAT3 by estrogen was observed both in
cells and in the hypothalamus), it is not known how this
process is accomplished in cells. Because ERs themselves are
transcription factors possessing no tyrosine kinase activity, a
tyrosine kinase must be activated upon estrogen administration. It was suggested that MAPK, Src kinase, and PI3K
pathways were required for estrogen activation of STAT3 in
cultured cells, but it is not clear how estrogen via ERs triggers
these pathways. We found that, in the hypothalamus, estrogen acutely activates Src kinase but does not affect JAKs
and other tyrosine kinases that are known to phosphorylate
STAT3 (Nie Y, unpublished data). Src kinase is a potent
tyrosine kinase known to directly bind to and phosphorylate
STAT3. This raised the possibility that Src kinase may be
the downstream effecter of estrogen signaling in STAT3
phosphorylation. However, how does estrogen activate Src
kinase through ERs?
How might estrogen and leptin regulate synaptology? One
possibility is that both leptin and estrogen regulate genes
involving synaptogenesis. Candidate genes such as postsynaptic density-95 (PSD-95), which regulates the balance between
excitatory and inhibitory synapses in the primary neuronal
cultures prepared from hippocampi of embryonic day (E)18/19
(85), and brain-derived neurotropic factor (BDNF), a neurotropin that regulates synaptic formation and function and has
an antiobesity effect (88). Both genes are regulated by estrogen
in vivo (3, 8, 100). PSD-95 is a protein that recruits the
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A variety of rodent models have been employed to probe the
importance of STAT3 to leptin action and reproductive function. In the first two of these, it was noted that mutation of the
STAT3 binding site on LRb promoted dramatic obesity, with
only modest impairment of fertility (6). In contrast, brain-wide
deletion of STAT3 resulted in obesity and infertility, suggesting that STAT3 is crucial for the regulation of reproduction as
well as metabolism (46). Indeed, this is to be expected given
that estrogen acts in part via STAT3. A role for STAT3 in
reproduction is also supported by the finding that STAT3
inhibitors, when injected into the hypothalamus, block the LH
surge (13). Thus, although STAT3 signaling by leptin may not
be essential for the regulation of reproduction, STAT3 itself is
required, presumably due to its importance in the estrogen
response. Recent findings in which deletion of STAT3 from all
LRb neurons resulted in obesity but not infertility suggest that
the role for STAT3 in reproduction may be due to estrogen
effects in non-LRb neurons (84).
wild-type littermates (32), revealing estrogen resistance in these
mice. Additional administration of estrogen in ER␣-null animals does not reduce either food intake or body weight (49).
Finally, ER␣-null mutants abolished the effect of estrogen to
reorganize the synaptology on POMC perikarya (47). Moreover, although both ER␣ and ER␤ affect fertility, ER␣ is not
required for follicle growth but is indispensable for ovulation,
suggesting a hypothalamic effect (36). Thus, it is reasonable to
suggest that estradiol’s effect on feeding, metabolism, synaptic
plasticity, and fertility is mediated by the ER␣ and potentially
involves STAT3. The function of estrogen and leptin in metabolism and reproduction seem to overlap.
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CROSS-TALK BETWEEN ESTROGEN AND LEPTIN
3.
4.
5.
6.
7.
8.
9.
Conclusion
Obesity is a major health problem in modern society, affecting more than one-quarter of all adults. Leptin regulates energy
homeostasis by acting as an indicator of body energy levels to
affect the behaviors of hypothalamic feeding neurons. Estrogen
is also a potent energy regulator and appears to interact with
leptin signaling. Both estrogen and leptin reduce appetite and
body fat and affect reproduction. This effect is achieved, in
part, through the rewiring of the melanocortin feeding system.
Because estrogen and leptin are both important for hypothalamic regulation of reproduction, a similar synaptic mechanism
may act in the nuclei associated with reproduction, i.e., the
AVPV and POA. Two genes, PSD-95 and BDNF, are both key
factors in synaptogenesis and are regulated by estrogen (3, 8,
100). PSD-95 and the associated protein AKAP79/150 are
critical for mediating PKA-induced phosphorylation of GluR1,
which increases the number and activities of GluR1 on the cell
surface (104). PSD-95-regulated GluR incorporation in the
synapses is an important mechanism underlying synaptic plasticity.
The molecular mechanism underlying the interaction between ERs and STAT3 is largely unknown. In cultured cells,
estrogen is able to activate STAT3 through various signaling
pathways in a nongenomic manner. Ligand-bound ERs are also
able to physically bind to STAT3. The ultimate consequence of
various interactions between estrogen and leptin signaling are
the transactivation of target genes. Such mechanisms may
allow estrogen to regulate energy homeostasis and synptogenesis independently of functional leptin and leptin receptors.
That is, estrogen and leptin signaling may interact through ERs
and STAT3 to regulate common target genes involved in
synaptogenesis in the hypothalamic regions related to energy
homeostasis and reproduction.
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