Clinical Science (2007) 112, 93–111 (Printed in Great Britain) doi:10.1042/CS20060150
R
E
V
I
E
W
Diet, obesity and diabetes: a current update
Celia G. WALKER, M. Gulrez ZARIWALA, Mark J. HOLNESS and Mary C. SUGDEN
Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, St Bartholomew’s and the Royal London
School of Medicine and Dentistry, Queen Mary’s Hospital, University of London, London, U.K.
A
B
S
T
R
A
C
T
The prevalence of obesity has been increasing at a rapid rate over the last few decades. Although the
primary defect can be attributed to an imbalance of energy intake over energy expenditure,
the regulation of energy balance is now recognized to be complex. Adipose-tissue factors play a
central role in the control of energy balance and whole-body fuel homoeostasis. The regulation
of adipose-tissue function, in particular its secretion of adipokines, is impaired by increases in
adipose mass associated with obesity, and with the development of insulin resistance and Type 2
diabetes. This review analyses adipose-regulated energy input and expenditure, together with the
impact of dietary macronutrient composition on energy balance in relation to susceptibility to
the development of obesity and Type 2 diabetes, and how these metabolic conditions may be
exacerbated by the consequences of abnormal adipose function. By gaining a greater understanding
of how energy balance is controlled in normal, and in obese and diabetic states, a more practical
approach can be employed to prevent and better treat obesity and metabolic disorders.
INTRODUCTION
Obesity is an accumulation of excess body fat such that
health might be impaired. A quantitative definition
of obesity is a BMI (body mass index) exceeding 30
kg/m2 . Obesity is one of the most prevalent disorders of
developed countries, and its incidence is increasing
rapidly. In England, the percentage of individuals classified as obese increased from 13.2 % to 23.6 % in men and
16.4 % to 23.8 % in women between 1993 and 2004. In
English children aged 2–10 years, the incidence of obesity
(using appropriate BMI for age and gender defined by
the UK National BMI percentile classification) increased
from 9.9 % to 13.1 % between 1995 and 2003 (reviewed
in [1]). Obesity, in particular central (visceral) obesity,
is associated with physiological changes which cause
or contribute to the development of diseases, including
Type 2 diabetes, hypertension and cardiovascular disease,
as well as non-alcoholic fatty liver disease, gall bladder
disease, osteoarthritis and some cancers [2–4]. Thus the
increasing incidence of obesity is particularly detrimental
because of its associated diseases which, in addition to the
Key words: adipokine, adipose-tissue nutrient transport, diabetes, dietary composition, insulin resistance, obesity.
Abbreviations: ACC, acetyl-CoA carboxylase; AgRP, agouti-related peptide; AMPK, AMP-activated protein kinase; AQP,
aquaglyceroporin; Apo, apolipoprotein; ARC, arcuate nucleus; BMI, body mass index; CART, cocaine- and amphetamine-regulated
transcript; CPT1, carnitine palmitoyl transferase 1; CRH, corticotrophin-releasing hormone; DAG, diacylglycerol; FA, fatty
acid; FAS, FA synthase; FATP, FA transporter protein; FoxO1, forkhead box-containing protein of the O superfamily; GLUT,
glucose transporter; GSIS, glucose-stimulated insulin secretion; HSL, hormone-sensitive lipase; ICV, intracerebroventricular;
IL6, interleukin 6; IRS, insulin receptor substrate; LBP, lipid-binding protein; ALBP, adipocyte LBP; LPL, lipoprotein
lipase; MBH, mediobasal hypothalamus; MCD, malonyl-CoA decarboxylase; MCH, melanin-concentrating hormone; MCR,
melanocortin receptor; α-MSH, α-melanocyte-stimulating hormone; NEFA, non-esterified FA; NPY, neuropeptide Y; PDC,
pyruvate dehydrogenase complex; PFK1, phosphofructo-1-kinase; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B;
POMC, pro-opiomelanocortin; PPAR, peroxisome-proliferator-activated receptor; PVN, paraventricular nucleus; SCD, stearoylCoA desaturase; SREBP1c, sterol-regulatory-element-binding-protein 1c; STAT3, signal transducer and activator of transcription
3; TAG, triacylglycerol; ATGL; adipose-tissue TAG lipase; TNFα, tumour necrosis factor α; UCP1, uncoupling protein 1; TZD,
thiazolidinedione; VLDL, very-low-density lipoprotein; VMN, ventromedial nucleus.
Correspondence: Professor Mary C. Sugden (email [email protected]).
C
2007 The Biochemical Society
93
94
C. G. Walker and others
concerns posed to the individual, cause a serious drain
on health systems as they require long-term expensive
treatment. It is estimated that the cost of treating obesityrelated diseases contributes 2–7 % of total national health
care costs in developed countries.
As the incidence of obesity rises rapidly, so does that
of Type 2 diabetes. In 2000, the incidence of diabetes
worldwide was 171 million; this figure is predicted to
rise to 366 million by 2030 (World Health Organization;
http://www.who.int/diabetes/). Although Type 2 diabetes is currently more prevalent in developed countries,
affecting 5–7 % of the UK population, its incidence is
also increasing in developing countries [5], perhaps linked
to a switch towards a more affluent lifestyle. Although
in developed countries the incidence of Type 2 diabetes
is greatest in people over the age of 65, its incidence is
rapidly increasing between the ages of 35–64. Since many
of the health and financial costs to society of obesity are
via the long-term treatment of diabetic complications [6],
the development of diabetes at this earlier age is important
as the likelihood of developing long-term complications
increases.
Although family, twin and adoption studies suggest
that the genetic contribution to BMI ranges from 60–84 %
[7], this alone is unlikely to account for the recent rise
in the incidence of overweight and obesity and its accompanying disorders. Several changes resulting from
modern lifestyle have contributed to the rapid increase.
These relate to both increased energy intake and decreased energy expenditure. In addition, other factors related to modern lifestyle (such as altered dietary composition) may affect the physiology of energy balance and
contribute further to the increased development of obesity [8,9]. The expansion of the adipose-tissue mass results
in deleterious effects on energy balance regulation. To
prevent the incidence of obesity accelerating at its current
rate, increasing emphasis is placed on understanding
the mechanisms by which long-term exposure of major
tissues and organs to high concentrations of nutrients, including glucose and lipids (particularly in combination),
cause tissue malfunction and obesity-related disease.
Genotype and phenotype contribute to
the predisposition to obesity and Type 2
diabetes
Throughout history, animals (including man) have evolved to cope with intermittent or inadequate food supply. Energy is stored efficiently as esterified lipid [TAG
(triacylglycerol)] in (white) adipose tissue when food
is abundant; adipocyte TAG is mobilized when energy
intake is insufficient to meet energy expenditure. Evolutionary pressure would have promoted effective storage
of energy when food was plentiful, together with physiological adaptations to promote survival when energy
intake was inadequate [10,11]. The evolutionary selection
C
2007 The Biochemical Society
of a specific genotype promoting these responses has been
termed the ‘thrifty genotype’ [10,12]. The occurrence and
apparent predominance of a thrifty genotype in humans
has resulted in a genetic predisposition which results in
easy excess energy storage as fat. The system controlling
body weight homoeostasis which evolved to cope with
food scarcity appears to be less effective at resisting the
challenge of excessive abundance of energy-dense food,
together with a lesser requirement for energy expenditure
because of reduced physical activity.
It has also been proposed that factors that impair nutrient supply in early life induce permanent changes in tissue
and organ function that conserve glucose and prioritize
development of key fetal organs such as the brain and
heart. This has been termed the ‘thrifty phenotype’ hypothesis [13]. Such alterations appear to be advantageous
for survival providing that the individual remains on a
poor diet throughout life. However, they may become
detrimental by altering the balance of nutrient disposition
towards storage away from disposal, and therefore predisposing to obesity when dietary intake is increased
relative to expenditure. Evidence supporting early life origins of obesity and insulin resistance have been recently
reviewed [14,15]. Some of these effects may be achieved
by epigenetic mechanisms that exert a stable influence
on gene expression, as reviewed elsewhere [16,17]. Epigenetic mechanisms offer one plausible explanation for
the recent epidemic of obesity, which has occurred during
a relatively short period over which substantial changes
in genes pools are unlikely.
ROLE OF ADIPOSE TISSUE IN FUEL
HOMOEOSTASIS
Adipose tissue is an energy-dense reservoir: in humans,
15 kg of body fat supplies sufficient calories for survival
for approx. 2 months [18]. Adipose tissue also has a remarkable capacity for expansion. As well as the ability
to increase cell numbers, individual adipocytes can alter
their volumes up to a 1000-fold, becoming engorged
with TAG [18]. In the fed state, insulin increases adipocyte TAG storage. This is achieved by augmenting
adipocyte glucose uptake [allowing the production of
glycerol 3-phosphate for FA (fatty acid) esterification
to form TAG as well as FA synthesis de novo] and by
direct effects to stimulate enzymes in the pathway for
esterification of incoming FA, generated locally via adipocyte LPL (lipoprotein lipase). FA transport into cells is
achieved via diffusion across the plasma membrane and
also via FA transporter proteins, of which two major
classes have been described: CD36 [FAT (FA translocase)/GPIV (glycoprotein IV)] and FATPs [(FA transporter proteins) FATP1–6]. Adipocyte lipid accretion is
enhanced by activation of the lipogenic transcription factor PPAR (peroxisome-proliferator-activated receptor) γ
Diet, obesity and diabetes
Figure 1 Impact of enlarged adipocytes on the regulation on nutrient handling
+, activation. FAO, FA oxidation.
[19–21], which is highly expressed in white adipocytes.
PPARγ activation promotes adipocyte differentiation,
enhances glucose uptake and its conversion into glycerol
3-phosphate, induces genes involved in lipogenesis and
regulates genes involved in insulin signalling (reviewed
[22]). TZDs (thiazolidinediones) are administered as
insulin-sensitizing agents in the treatment of Type 2 diabetes. These PPARγ ligands reverse insulin resistance by
reducing systemic NEFA (non-esterified FA) levels by a
combination of direct and indirect mechanisms including:
(i) promotion of adipocyte differentiation leading to increased TAG storage; (ii) retention of FAs in adipose
tissue by activation of FATP1, CD36, PEPCK (phosphoenolpyruvate carboxykinase) and glycerol kinase;
(iii) enhancement of adipocyte glucose disposal by induction of c-Cbl-associating protein and GLUT4 (glucose
transporter 4); and (iv) regulation of adipokine gene expression [23]. A decrease in ectopic TAG, and circulating
NEFAs and TAG, is accompanied by an increase in
adipose TAG synthesis and adipose mass [24]. The role of
adipose tissue and insulin sensitivity is therefore related
to its FA- and TAG-buffering capacity, which is impaired
both in obesity and in lipodystrophy [25,26].
Enlarged adipocytes release increased amounts of FAs;
as they are insulin-resistant, they are unable to respond
effectively to insulin with inhibition of lipolysis [27–30]
(Figure 1). There may also be a ‘spillover effect’ resulting
from saturation of the capacity for TAG storage [31,32].
Increased circulating FAs and ectopically stored fat reduce the insulin sensitivity of non-adipose tissues (Figure 1). In addition, although acute exposure to FAs facilitates GSIS (glucose-stimulated insulin secretion) by the
pancreatic β-cells, more long-term overexposure (particularly in combination with elevated glucose) (glucolipotoxity) impairs GSIS [33] (Figure 1). However, insulin
resistance in adipose tissue may not be as detrimental as
might be predicted. Mice with an adipose-tissue-specific
knockout of the insulin receptor (FIRKO mice) resist
diet-induced obesity, are whole-body insulin-sensitive
and show increased longevity [34].
Adipocytes can rapidly transform from actively storing to actively releasing energy [35–37]. In response to
lipolytic stimulation, adipocytes hydrolyse stored TAG.
Until recently, HSL (hormone-sensitive lipase) was presumed to be the rate-limiting enzyme involved in adiposetissue lipolysis; however, recent observations using HSLnull mice led to the characterization of a newly discovered
adipose TAG lipase (ATGL), an enzyme expressed predominantly in (white and brown) adipose tissue and
specifically localized in the adipose-tissue lipid droplet
[38,39] (Figure 1). A lipid-droplet-associated protein
CGI-58/ABHD5 is responsible for efficient ATGL activity; antisense RNA-mediated suppression of CGI-58
expression in 3T3 adipocytes inhibits TAG mobilization
C
2007 The Biochemical Society
95
96
C. G. Walker and others
[40]. HSL hydrolyses DAG (diacylglycerol) generated
by ATGL to mono-acylglycerol and subsequently to
FAs and glycerol. FAs and glycerol are released into the
circulation. In a recent study [41], the relative contributions of ATGL and HSL to adipose tissue lipolysis
was examined by comparing samples from obese and
non-obese subjects. The authors concluded that HSL
mediates catecholamine-stimulated lipolysis in white
adipose tissue, whereas ATGL could be responsible for
basal TAG lipolysis [42].
FAs are used for oxidative ATP production in a range
of tissues; glycerol is used for hepatic gluconeogenesis, a
process involving its conversion into glycerol 3-phosphate by hepatic glycerol kinase (Figure 1). FAs also
act as ligands for transcription factors which regulate
lipid breakdown, the lipo-oxidative transcription factors
PPARα and PPARβ/δ [43] (Figure 1). Circulating NEFA
concentrations therefore affect substrate utilization by
altering gene expression to favour FA oxidation. For
example, hepatic expression of PPARα is increased during
fasting, directly enhancing expression of genes involved
in FA uptake (FATP), β-oxidation (acyl-CoA oxidase)
and ω-oxidation [44]. PPARα also enhances PDK4 (pyruvate dehydrogenase kinase 4) expression which, through
suppressing pyruvate oxidation, facilitates gluconeogenesis [45]. A study using the pharmacological PPARα
agonist WY14643 and PPARα-null mice demonstrated
that PPARα activation up-regulates expression of hepatic
genes involved in gluconeogenesis from glycerol, including cytosolic and mitochondrial glycerol 3-phosphate
dehydrogenase, glycerol kinase and AQP (aquaglyceroporin) 3 and 9 [46] (Figure 1).
The discovery of the glycerol transporter AQP7 highlighted the previously underappreciated role of glycerol
transport in the development of obesity [47,48]. AQP7
is highly expressed in adipose tissue and is prerequisite
for efficient glycerol release from adipose tissue during
fasting. Adipocyte glycerol content is elevated 3-fold, and
measurements in adipocytes of comparable size showed
a 65 % reduction in glycerol permeability in AQP7-deficient adipocytes [48]. Rates of TAG lipolysis and FA synthesis are not impaired, indicating that the accumulation
of intracellular glycerol does not feedback to inhibit TAG
lipolysis [48]. AQP7 mRNA expression in adipose tissue
is enhanced by insulin deficiency and suppressed by elevating insulin on refeeding after starvation [49] AQP7
mRNA expression in mesenteric adipose tissue is increased in insulin-resistant db/db mice [49], which exhibit
impaired leptin receptor function. Thus removal of the restraint on lipolysis imposed by insulin under conditions
of insulin deficiency or resistance is coupled with increased adipocyte AQP7 expression. A negative insulinresponse element has been identified in the mouse [49]
and human [50] AQP7 gene promoter.
In the fed state, AQP7-knockout mice become progressively obese with aging, with TAG-engorged adipo
C
2007 The Biochemical Society
cytes [47,48]. The development of obesity caused by
AQP7 deficiency was accompanied in one AQP7−/−
mouse line by severe insulin resistance and glucose intolerance [47]. Nevertheless, these mice have increased
susceptibility to the rapid development of obesity in response to a high-fat/high-sucrose diet [47]. Thus glycerol
retention within adipose tissue promotes expansion of
the adipose tissue mass in the fed state and adequate
AQP7 expression/function is important to restrict excessive TAG accumulation in adipocytes under anabolic
conditions. The mechanism by which glycerol accumulation promotes adipocyte hypertrophy appears to involve
enhancement of adipocyte glycerol kinase activity [47].
Both glycerol kinase activity and oleic acid uptake are
increased by AQP7-knockdown in 3T3-L1 adipocytes
[47].
AQP7 is a direct PPARγ target gene [19,49]. Differentiated mouse and human adipocytes respond to TZDs
in culture with an increase in adipocyte AQP7 mRNA expression [46,50]. AQP7 mRNA expression in differentiated adipocytes is also increased by the exposure to
the PPARβ/δ agonist L165041 in culture [46], but the
overall physiological significance of PPARβ/δ signalling
in adipocytes has not been elucidated.
ADIPOSE-REGULATED ENERGY BALANCE
Adipokines, produced and released from adipose tissue,
regulate a range of metabolic, endocrine and immune
functions that affect energy intake and expenditure and
nutrient utilization [18,35,51]. Excess visceral fat is specifically associated with Type 2 diabetes, and insulin resistance is proportional to visceral fat mass [52,53], suggesting that adipokines secreted disproportionately from
visceral fat are, in part, responsible for the loss of adiposeregulated energy balance.
An adequate amount of adipose tissue is also essential
for metabolic homoeostasis [36,54]: although obesity is
intimately linked to insulin resistance and Type 2 diabetes,
these conditions also develop in people with lipodystrophies [54] and occur in rodent models of lipodystrophy
[24,54,55]. These findings have confirmed adipose tissue
and its secreted adipokines in the axis between the detection of nutrient status and the maintenance of energy
balance [18,35,56].
Leptin has been largely responsible for highlighting
the role of adipose tissue in energy balance. Both ob/ob
(leptin-deficient) and db/db (leptin-receptor-deficient)
mice exhibit early hyperinsulinaemia and hyperphagia
followed by obesity, hyperglycaemia and diabetes [57].
Leptin regulates appetite and energy expenditure, as well
as altering substrate utilization [35,58]. In mice, insulin
resistance associated with lipo-atrophy is reversed if adipose tissue is transplanted from wild-type mice [59], but
not if it is obtained from ob/ob mice [60]. Exogenous
leptin administered to severely lipo-atrophic humans and
Diet, obesity and diabetes
Figure 2 Influence of adipokines on insulin signalling/action
+, activation; −, inhibition.
mice also improves insulin sensitivity [55]. With the exception of the ob/ob mouse, systemic leptin concentrations are generally proportional to adipose tissue mass
[61–66]. Leptin also responds to nutritional state, decreasing with fasting and restored by re-feeding. Glucose,
insulin and increased adipocyte glucose metabolism
stimulate leptin secretion [67–72]. Conversely, some FAs
[73,74] and an increased rate of lipolysis [75–78] inhibit
leptin secretion. All of these factors are altered in obesity
and diabetes, therefore affecting the regulation of leptin
levels.
Visfatin (discovered as a cytokine-like growth factor
in lymphocytes, termed pre-B-cell colony-enhancing factor), as its name implies, was thought to be preferentially
expressed and secreted by visceral fat, but is now known
also to be secreted from subcutaneous adipose tissue
[79,80]. Rather than inducing insulin resistance, as might
be inferred from its expression in visceral fat, visfatin
possesses insulin-mimetic activity [81]. The binding affinity of visfatin for the insulin receptor resembles that of
insulin, and visfatin causes phosphorylation of various
insulin signalling proteins, including IRS (insulin-receptor substrate) 1 and 2 (Figure 2). Visfatin does not compete with insulin for binding to the insulin receptor, so it is
likely that these proteins interact with different receptor
domains. Circulating visfatin levels are lower than those
of insulin and are unaffected by feeding or fasting. Nevertheless, plasma visfatin concentrations correlate positively with body fat and thus increase during the development of obesity. Individuals with Type 2 diabetes
have elevated plasma visfatin concentrations [82], as do
pregnant women with gestational diabetes [83]. Mouse
models of obese Type 2 diabetes and diet-induced obesity have higher visfatin levels and increased visfatin
expression in visceral fat [80,81]. Further details of the
actions of visfatin are reviewed elsewhere [84].
Decreased concentrations of adiponectin, another prominent adipokine, are associated with lowered insulin
sensitivity [85,86]. Lipo-atrophic insulin-resistant mice
are deficient in adiponectin [86]. Adiponectin-knockout
mice develop severe diet-induced insulin resistance [87].
Replenishment of leptin in combination with adiponectin
elicits a complete reversal of insulin resistance in lipoatrophic mice, compared with partial reversal observed
with adiponectin or leptin individually [86], indicating
that these two adipokines produce a protective effect
on insulin sensitivity (Figure 2). Conversely to leptin,
levels of adiponectin are reduced in obesity [88,89], an
effect attributed to increased release of TNFα (tumour
necrosis factor α) [90]. In vitro, adiponectin expression
is suppressed by TNFα, which inhibits the adiponectin
promoter [91].
In obese patients, increased levels of inflammationrelated adipokines, including TNFα, led to the suggestion
that obesity is a state of chronic low-grade inflammation
[92,93]. Trayhurn and colleague [92,93] also developed
the hypothesis that relative hypoxia associated with expansion of the adipose-tissue mass underlies the growing
inflammatory response within the adipocyte. It is proposed that, as the adipose mass expands due to adipocyte
hypertrophy with hyperplasia, adipocytes distinct from
the vasculature become relatively hypoxic. Inflammation
in white adipose tissue is also augmented through macrophage infiltration as the adipose mass expands. In
C
2007 The Biochemical Society
97
98
C. G. Walker and others
Figure 3 Regulation of energy intake
VMH, ventromedial hypothalamus.
non-diabetic human subjects, fat accumulation correlates
closely with markers of systemic oxidative stress. Similar
responses are observed in adipose tissue of mouse models
of obesity, including obese KKAy mice, which show
enhanced mRNA expression of components of the
NADPH oxidase complex and down-regulation of expression and activities of antioxidant enzymes. Exposure
of fully differentiated adipocytes to ROS (reactive oxygen
species) decreases PPARγ and adiponectin mRNA expression, while increasing mRNA expression of inflammatory cytokines [PAI1 (plasminogen-activator inhibitor
1) and IL6 (interleukin 6)]. These effects are reversed by
antioxidant treatment. Chronic treatment of KKAy mice
with the NADPH oxidase inhibitor apocynin reduces
markers of oxidative stress in white adipose tissue, increases adiponectin and decreases TNFα [94].
A key consequence of expansion of the adipose-tissue
mass may be its inability to detect metabolic status and
release cytokines inappropriately. An impaired ability of
the adipocyte to sense nutritional state in obesity affects
the acute regulation of adipokine secretion, which in turn
regulates energy balance. For example, fasting ordinarily
produces a dramatic decline in leptin levels: this response is blunted in obese rodents [61,69,95]. When nutritional stimulation is mimicked by euglycaemic/hyperinsulinaemic clamp conditions, a loss in whole-body
glucose tolerance is associated with a decreased leptin
response [96–98]. Adiponectin responses to a mixed meal
are unchanged in lean subjects, but increased from a lower
baseline in obese subjects to a level higher than in the lean
C
2007 The Biochemical Society
subjects [99]. When nutritional stimulation is achieved
under hyperinsulinaemic/euglycaemic clamp conditions,
serum adiponectin is again unaltered in lean subjects,
but decreased in obese subjects [100]. It is yet to be
determined why adiponectin secretion is more responsive
in the obese state, and why the responses vary with
different methods of nutritional stimulation.
Central regulation of energy intake
Specific feeding centres in the brain control food intake by
stimulating appetite or feelings of satiety. These feeding
centres are regulated by hormonal and nutritional signals
from the body that, in turn, are altered by nutritional
state [56]. The accelerated growth of obesity in modern
societies indicates that the homoeostatic mechanisms that
maintain weight stability may be malfunctioning, such
that appetite controlling mechanisms are compromised.
The hypothalamus, located in the middle of the base
of the brain, houses a dense population of receptors for
hormonal and metabolite control of satiety and appetite
[56,101]. The signalling pathways work rapidly using
agonist and antagonist systems in which there is redundancy [10]. Several neuropeptides within the ARC
(arcuate nucleus) and PVN (paraventricular nucleus)
of the hypothalamus stimulate (orexigenic) or inhibit
(anorexigenic) feeding [56,102] (Figure 3). Orexigenic
peptides include NPY (neuropeptide Y), AgRP (agoutirelated peptide) and MCH (melanin-concentrating
hormone) [103,104] (Figure 3). The NPY/AgRP neurons
respond to afferent signals reflecting energy deficit, such
Diet, obesity and diabetes
as hypoglycaemia. Levels of orexigenic peptides increase
during fasting, where systemic glucose levels can fall by 1–
2 mmol/l [104–107], and are chronically elevated in obese hyperglycaemic rodents (e.g. ob/ob mice) [105]. In
rodents, central administration of both NPY and MCH
stimulates hyperphagia, and overexpression of MCH results in obesity [105,108–110], whereas food intake
decreases the expression of NPY, MCH and AgRP
[105,106,108,109]. Genetic variation in the human
AgRP gene (Ala67Thr) is associated with inherited
leanness [111]. NPY-null mice have normal body weight
and adiposity, suggesting that signalling via AgRP (or
other orexigenic pathways) can compensate.
The melanocortin system, which promotes negative
energy balance, is inhibited by high levels of AgRP and
MCH and activated by anorexigenic peptides, the most
potent of which is α-MSH (α-melanocyte-stimulating
hormone), derived from POMC (pro-opiomelanocortin)
by post-translational processing and released from
POMC neurons [103,104]. Melanocortin peptides, such
as α-MSH and corticotropin (adrenocorticotropin), bind
to melanocortin receptors (MC3R and MC4R) expressed
within the VMN (ventromedial nucleus) of the hypothalamus. Many POMC neurons also produce a neuropeptide precursor protein, CART (cocaine- and amphetamine-regulated transcript), which is processed to yield
anorectic peptides. The action of CART appears to be
mediated by neurons within brain areas that process stress
and reward signals, namely the third and forth ventricles.
The synthesis of α-MSH and other anorexigenic peptides,
including CART and CRH (corticotrophin-releasing
hormone), is decreased during fasting [112,113]. Mutations causing a deficiency in POMC or the melanocortin
receptor MC4R are the most common cause of genetic
obesity in humans [114]. MC4R agonists are in development as an obesity therapy [1].
REGULATION OF ENERGY INTAKE BY
NUTRIENTS
The hypothalamus responds to varying circulating concentrations of nutrients, in particular glucose and FAs.
The hypothalamus also responds to insulin, leptin and
the predominantly stomach-derived orexigenic peptide
ghrelin (Figure 3). All of these signals interact with many
of the orexigenic and anorexigenic signalling systems
that translate a chemical response to food intake into a
neural response, which then regulates subsequent food
intake [103,104]. Glucostatic and lipostatic mechanisms
have been formulated: the former proposed that circulating glucose is the main signal to the hypothalamus of
the body’s nutritional status, whereas the latter proposed
that lipids are of primary importance. When glucose is
administered via ICV (intracerebroventricular) injection,
blood glucose levels decrease, indicating a direct central
action [115]: glucose also modulates both insulin secretion from the pancreatic β-cell and leptin secretion
from the adipocyte [67], and so direct effects are reinforced. The glycaemic index, a measure of the ability of
nutrients to elevate glycaemia, is inversely proportional
to the effect on subsequent food intake in the short
term [116]. By virtue of its rapid conversion into fat
(see below), fructose has a low glycaemic index (5-fold
lower than that of glucose) and thus induces satiety
more slowly than consumption of isocaloric amounts of
glucose, resulting in increased food intake.
The lipostatic hypothesis, which originally proposed
that circulating lipids were of primary importance for hypothalamic nutrient sensing, has evolved into the adipostat hypothesis. Here lipid storage, rather than the
systemic lipid concentration, is proposed as the major
regulator (reviewed in [117]). Nevertheless, central
administration of oleic acid inhibits food intake [118] and,
in the short term, FAs potentiate GSIS [119].
Substrate competition is integral to energy homoeostasis. The Randle (glucose/FA) cycle [120] is conventionally viewed as the dominance of FAs over glucose
as the preferred energy substrate, with suppression of
glucose oxidation via inhibition of the PDC (pyruvate
dehydrogenase complex), inhibition of glycolysis via inhibition of PFK1 (phosphofructo-1-kinase) and feedback
inhibition of glucose uptake/phosphorylation by glucose
6-phosphate. When glucose is abundant and insulin concentrations are high, a ‘reverse glucose/FA cycle’ operates
whereby glucose utilization blocks FA oxidation by its
effect to increase malonyl-CoA. This reverse cycle, developed by McGarry and colleagues [121], has been comprehensively reviewed [122]. By analogy to the operation
of the glucose/FA cycle and the ‘reverse glucose/FA
cycle’ in muscle, substrate-led interactions also may influence hypothalamic nutrient sensing to modify feeding
behaviour. Both inhibition of hypothalamic lipid oxidation and central inhibition of the lipogenic enzyme FAS
(FA synthase), the enzyme complex that utilizes malonylCoA to form FAs, suppress feeding (reviewed in [117]).
Recently, it has been demonstrated that molecular disruption of the hypothalamic nutrient-sensing mechanism
induces obesity [123]. Administration of adeno-associated virus expressing MCD (malonyl-CoA decarboxylase), which depletes malonyl-CoA and decreased longchain FA-CoA in the mediobasal hypothalamus, blunted
the hypothalamic response to increased lipid availability,
caused hyperphagia and induced a progressive increase in
fat mass.
Within the context of the aetiology of Type 2 diabetes,
hypothalamic sensing of both glucose (via hypothalamic
pyruvate metabolism) [115] and FAs is required to optimize glucose homoeostasis [124], with major actions on
hepatic glucose fluxes. Interventions such as exercise,
which modify systemic lactate+pyruvate and FA levels,
may therefore not only influence energy expenditure (see
C
2007 The Biochemical Society
99
100
C. G. Walker and others
below) but also energy input. Understanding the biochemical steps involved in hypothalamic nutrient sensing
is fundamental to evaluating whether abnormalities in this
mechanism contribute to obesity. Chronic activation of
ACC (acetyl-CoA carboxylase) within the hypothalamus
in obesity, perhaps because of chronic exposure to high
levels of circulating glucose, via long-term suppression
of FA oxidation secondary to increased malonyl-CoA
levels, could cause hypothalamic insulin resistance due
to the accumulation of lipid intermediates in a manner
reminiscent of that seen in skeletal muscle.
Central actions of insulin and leptin
Taking nutrient control to a secondary level, the interplay
between POMC/CART and NPY/AgRP neurons in controlling energy homoeostasis, and thus obesity levels,
is emphasized by their responses to insulin and leptin,
whose secretion from the pancreatic β-cell and the adipocyte respectively, occurs in response to nutrient abundance. Central insulin administration decreases food intake
[125]; conversely, a reduction in hypothalamic insulin
receptor expression increases food intake [126]. A small
molecular-mass insulin-receptor agonist suppressed food
intake when given either centrally or peripherally [127].
Insulin resistance in obesity can be accompanied by islet
compensation, resulting in insulin hypersecretion [128].
Long-term exposure of the hypothamus to high insulin
levels could down-regulate or desensitize the hypothalamic insulin receptor, resulting in increased food
intake. Since visfatin binds to insulin receptors, it is possible that visfatin could influence appetite control and body
weight regulation. Mice homozygous null for the visfatin
gene die during embryogenesis, but heterozygotes with
30 % lower circulating visfatin concentrations have high
plasma glucose levels [81], suggesting a physiological role
in energy homoeostasis.
Leptin, administered as a continuous subcutaneous
infusion, as repeated intraperitoneal injections or as a
single intravenous injection, decreases food intake and
body weight in lean mice in a dose-dependent manner
[129–131]. As the highest density of leptin receptors exists
in the hypothalamus, this area of the brain is believed to
co-ordinate the major functions of leptin [132]. A single
leptin dose administered directly into the lateral ventricle
of mice by ICV cannulation decreases food intake [129].
Increases in hypothalamic leptin, through central administration or feeding, decrease the expression of NPY,
MCH and AgRP [103–106,109], whose levels increase
during fasting [104–107], but leptin administration during
fasting prevents activation of orexigenic neurons and
increases expression of orexigenic peptides [107,113].
Leptin administered during fasting also normalizes the
decreased expression of anorexigenic peptides, including
CART and CRH [113,133,134]. A loss of leptin receptors
in the hypothalamus, as seen in db/db mice or through
the use of aurothioglucose [135], causes hyperphagia and
C
2007 The Biochemical Society
increased weight gain [57,136]. This control may be mediated by NPY, as central administration of both insulin
and leptin activate NPY neurons [107]. The neuronal
signalling events triggered by fasting can be opposed by
the administration of leptin, insulin or glucose which
prevent activation of orexigenic neurons and increased
expression of such orexigenic peptides [107,113].
Interactions between insulin, leptin
and ghrelin
Plasma ghrelin levels increase during fasting, decrease
during food ingestion and have been proposed to contribute to the aetiology of human obesity. Ghrelin
secretion and circulating ghrelin levels are reciprocal to
those of insulin in relation to food intake, glucose loading
and glucose infusion [137–140]. Hyperphagia associated
with diabetes is rapidly reversed by the administration
of a ghrelin-receptor antagonist [141]. The postprandial
decrease in systemic ghrelin levels is slower in obese than
in lean subjects, and this may contribute to differences in
food intake [142]. Grossly elevated ghrelin levels are
found in Prader–Willi syndrome, which is associated
with hyperphagia and obesity ([143]; reviewed in [144]).
Human subjects that receive ghrelin have a 28 % increase
in food intake [145]. These findings suggest that failure to
suppress ghrelin levels postprandially may lead to hyperphagia and obesity. Ghrelin and leptin are suggested to
regulate energy homoeostasis as mutual antagonists on
hypothalamic neurons that regulate feeding behaviour,
but ablation of ghrelin in ob/ob mice fails to rescue the
obese hyperphagic phenotype, indicating that the ob/ob
phenotype is not a consequence of ghrelin action unopposed by leptin [146].
Regulation of hypothalamic AMPK
(AMP-activated protein kinase) activity
AMPK is a prominent cellular ‘fuel gauge’ (reviewed in
[147]). AMPK is activated by depletion of ATP: allosteric
activation when it binds AMP and/or through AMPfacilitated phosphorylation by activation of the protein
kinases, including LKB1 and CaMKK2β (Ca2+ /calmodulin-dependent protein kinase kinase 2β), or by inhibition of PP2C (protein phosphatase 2C) [148]. AMPK
exists as a heterotrimeric complex of a catalytic α-subunit
(encoded by two genes, α1 and α2), a regulatory βsubunit (also encoded by two genes, β1 and β2) and a
γ -subunit (encoded by three genes, γ 1, γ 2 and γ 3).
Increased glucose, insulin and leptin, which curtail
feeding behaviour, all decrease hypothalamic AMPK activity, whereas fasting increases hypothalamic AMPK
activity [149]. Hypothalamic activation of the α2 isoform
of AMPK decreases in response to glucose, insulin and
leptin, and bidirectional changes in hypothalamic α2AMPK activity are sufficient to modulate feeding behaviour [149]. AMPK may therefore co-ordinate nutritional
Diet, obesity and diabetes
signals from the periphery to neuronal signalling to
feeding behaviour (reviewed in [150]). An involvement of
α2-AMPK is particularly compelling for the anorexigenic
action of leptin (see [150]). Systemic or central leptin
administration decreases α2-AMPK activity selectively in
the ARC and PVN and, when this decrease is abrogated
by hypothalamic delivery of an adenovirus expressing a
constitutively active form of AMPK, food intake is no
longer decreased by leptin. Overexpression of hypothalamic AMPK increases expression of NPY, AgRP and
MCH [149]. It is not yet known how leptin decreases
AMPK activity in the ARC, but signalling events may
include stimulation of STAT3 (signal transducer and
activator of transcription 3), PI3K (phosphoinositide 3kinase) and MAPK (mitogen-activated protein kinase)
[151,152], and/or inhibition of the protein/lipid phosphatase PTEN (phosphatase with tensin homology; a
potent inhibitor of PI3K signalling) [153]. Nevertheless,
decreased ARC activity of AMPK could lead to increased
active (dephosphorylated) ACC, increased malonyl-CoA
concentrations, decreased FA oxidation and accumulation of long-chain acyl-CoA. Chronic increases in glucose, insulin and leptin, as seen in obesity and diabetes,
are not associated with the decreases in orexigenic and
increases in anorexigenic peptides seen in response to
acute increases in these agents [96-98,103,154,155], suggesting that signalling to AMPK may be affected.
FoxO1 (forkhead box-containing protein of the O
subfamily 1) regulates metabolism in a PI3K-dependent
manner [156]. Interestingly, delivery of adenovirus encoding a constitutively nuclear mutant FoxO1 to the
hypothalamic ARC results in a loss of ability of leptin
to curtail food intake, and FoxO-1 and STAT3 exert
opposing actions on expression of Agrp and Pomc [157].
As FoxO1 is considered to mediate stress resistance, it
was suggested that mechanisms to preserve body weight
might be part of an ancestral stress resistance pathway,
which might explain why mammals are better predisposed to preserve body weight than to lose it [157].
ADIPOSE-REGULATED ENERGY
EXPENDITURE
Energy is expended in supporting the body’s basic cellular functions (resting metabolic rate), in digesting and
assimilating food, by physical activity and during dietinduced thermogenesis [158]. Alterations in food intake
are mostly compensated by subsequent adjustments in
energy expenditure and changes in appetite [12]. The
modern lifestyle is often characterized by a decrease in
voluntary movement (exercise and incidental activity)
[9]. Approx. 25 % of American children are classified as
completely sedentary [159]. This clearly contributes to
increased incidence of obesity and is largely influenced by
environmental factors directly resulting from the modern
lifestyle. However, a genetic component also influences
an individual’s activity level; genetic factors account for
78 % of variance in physical activity [160]. In addition
to exercise altering the energy intake to energy expenditure ratio, exercise increases insulin sensitivity which has
additional beneficial effects on the regulation of body
weight homoeostasis and on the prevention of Type 2 diabetes. However, these improvements in insulin action
occur independently of changes in adiponectin levels or
of other adipokines, including leptin and TNFα, and consequently their effects on energy balance by central and
peripheral mechanisms. Involuntary energy expenditure
encompasses all other forms of energy expenditure. This
can be influenced by environmental factors (e.g. temperature and dietary modification) and genetic factors, which
can alter the response or the capacity to respond to environmental change. Sympathetic neural control, as well
as signalling molecules, can alter the rate of thermogenesis
in response to altered environment. Genetic differences
in energy expenditure have been demonstrated in animal
models. The obese ob/ob mouse, when restricted to the
same energy intake as a wild-type mouse, will exhibit
increased weight gain [57]. Factors governing this difference in energy expenditure are an attractive target for
weight-loss drugs. Although many monogenic forms
of obesity have been identified in humans, including
defects in the genes for leptin, the leptin receptor, POMC
and the melanocortin system [114], all involve genes
controlling appetite and satiety (energy intake). Few gene
defects have as yet been discovered which affect energy
expenditure [114]. MCH-null mice are lean, hyperactive,
hypermetabolic, resistant to diet-induced and agingassociated obesity and have a reduced visceral fat mass
[161].
Leptin-deficient ob/ob mice not only have increased
energy intake, but also decreased body temperature
and energy expenditure [57]. This suggests that neuronal
control of energy intake and energy expenditure is
closely linked. Pair-feeding experiments indicate that the
effects of leptin on weight reduction cannot be explained
by decreased food intake alone [162,163]. Leptin treatment of ob/ob mice corrects the abnormally low body
temperature of these mice, but does not affect body temperature of lean mice [130,164]. Similarly, leptin treatment
increases energy expenditure in ob/ob, but not lean, mice.
In each case, the increase in energy expenditure observed
in ob/ob mice returns their rate to that of control mice
[164,165]. Conversely, central administration of leptin to
lean mice prevents the decrease in energy expenditure
normally associated with fasting [166]. Whereas normal
fasting reduces lean body mass as well as adiposetissue mass, leptin treatment specifically targets adipose tissue [130,163,166,167]. Experimental hyperleptinaemia increases glycerol, but not FA, levels. This
suggests that FAs are metabolized at the same rate
as they are generated by lipolysis, whereas fasting- or
C
2007 The Biochemical Society
101
102
C. G. Walker and others
starvation-induced lipolysis are associated with an increase in circulating glycerol levels and increasing circulating FA levels [58]. Leptin levels therefore manipulate
whole-body substrate utilization.
A recent study [168] demonstrated that a single alteration in adipose-tissue physiology can alter the character of the leptin/body weight regulation system. Overexpression of UCP1 (uncoupling protein 1), which
increases thermogenesis, in epididymal adipose tissue of
obese mice produces a rapid (3 day) reduction in adiposetissue leptin expression and circulating leptin concentrations. This was associated with a significant decrease
in NPY expression and a trend for increased POMC
expression and decreased food intake. A leptin-tolerance
test showed that UCP1-overexpressing mice exhibited
increased sensitivity to leptin. Thus the characteristics of
the leptin signalling system in obese mice can be reset by
changing a single aspect of adipose physiology.
The role adiponectin plays in the regulation of energy
balance is less clear than that of leptin. Despite the opposing regulation of leptin and adiponectin, adiponectin
injections decrease fat pad weight, however, unlike leptin,
without a change in energy intake [86]. Direct ICV administration of adiponectin reduces body weight through
an increase in energy expenditure, suggesting that the
latter is partially centrally controlled [169]. Adiponectin
administration lowers plasma glucose levels by suppressing hepatic glucose production and increasing glucose
utilization [85,86,170], and also enhances both FA oxidation and glucose utilization by skeletal muscle via
AMPK activation [171]. Increased substrate utilization
is associated with increased expression of genes involved
in energy dissipation and an increased body temperature,
leading to the increased energy expenditure [86].
Not all adipokines may promote positive effects on
insulin sensitivity and whole-body metabolism. These
include TNFα and IL6 produced from the enlarged and
inflamed adipose tissue mass (reviewed in [32,172]). It
remains to be determined whether visfatin has a role in
energy expenditure.
INFLUENCE OF DIETARY MACRONUTRIENT
COMPOSITION ON SUSCEPTIBILITY TO
OBESITY AND DIABETES
Dietary recommendations are that between 45–65 % of
energy input should be derived from carbohydrates,
20–30 % from fat and 10–35 % from protein, with a
maximum of 25 % of total energy from added sugars
(Institute of Medicine of the National Academies; http://
www.iom.edu/report.asp?id = 4340). As the cause of
obesity is energy intake in excess of expenditure, the role
of diet in the increased incidence of obesity is to an extent
clear. However, the role that changes in diet have played
in the increase in incidence of obesity, insulin resis
C
2007 The Biochemical Society
tance and Type 2 diabetes is more complex. In susceptible individuals, alterations to the constituents of the diet
(increased simple sugars, saturated fats and energy density) may promote the development of insulin resistance,
diabetes and obesity independently of an increased energy
intake [173–175]. A clearer understanding of this aspect
of regulation may lead to the more logical design of diets
to help manage and prevent obesity and diabetes.
Dietary glucose and fructose and
consequences of their excess
The predominant dietary sugars are glucose, fructose,
sucrose, lactose and maltose. The monosaccharides glucose and fructose are absorbed directly and enter cells via
specific transporters (GLUT1, GLUT2 and GLUT4 for
glucose, and GLUT5 for fructose). GLUT1 is ubiquitous,
GLUT 2 is found in liver and the pancreatic β-cell,
and GLUT4 is abundant in skeletal muscle and adipose
tissue. Although GLUT5 is expressed at low levels in
several tissues, it is expressed at high levels in liver, the
most important site of fructose breakdown.
Metabolic fates of glucose and fructose, in addition
to degradation for ATP production, include storage as
glycogen or conversion into FAs. Under conditions of
a sustained surplus of glucose, acetyl-CoA production
from glucose via the PDC may exceed the requirements
for ATP production via the tricarboxylic acid cycle, with
resultant accumulation of citrate. Citrate, on exit from the
mitochondria, will allosterically activate the regulatory
lipogenic enzyme ACC. Cleavage of citrate by ATPcitrate lyase provides carbon to fuel rates of malonyl-CoA
formation. If malonyl-CoA synthesis exceed malonylCoA disposal via FAS and MCD, the resultant elevation
of malonyl-CoA concentration blocks oxidation of
dietary FA at the level of CPT1 (carnitine palmitoyltransferase 1), the expression of which in muscle is regulated
by PPARα. Suppression of CPT1 promotes FA partitioning from oxidation towards esterification. Muscle
malonyl-CoA concentrations are elevated in models of
rodent obesity [176,177], suggesting that obesity favours
the operation of the ‘reverse glucose/FA cycle’. In
obesity or situations of nutrient excess, elevated malonylCoA levels, possibly in conjunction with impaired FA
oxidation, can cause intracellular accumulation of lipidderived compounds that interfere with the mechanisms
that optimize energy homoeostasis. Prolonged exposure
to excess glucose also up-regulates the lipogenic transcription factor SREBP1c (sterol-regulatory-elementbinding-protein 1c) and key genes encoding lipogenic
enzymes in muscle [178,179], permitting an increased
capacity for FA synthesis. Knockout mice lacking the
ACC isoform found in muscle (ACC2) exhibit decreased
muscle malonyl-CoA levels and increased FA oxidation
[180].
An inability to increase reliance on fat oxidation during
fasting, despite elevated plasma FA, may be a hallmark of
Diet, obesity and diabetes
insulin resistance associated with obesity [181]. Similarly,
the increase in FA oxidation that normally occurs in response to exercise or β-adrenergic stimulation is diminished in obese and/or diabetic subjects (reviewed in
[182]). The inability of muscle to switch between
metabolic fuels (glucose compared with lipid) as oxidative
substrate has been termed ‘metabolic inflexibility’ [181].
The action of hyperglycaemia to suppress fat oxidation
in myotubes derived from human quadriceps is variable,
as is the ability of myotubes to respond to increased
FA concentrations with increased FA oxidation, with a
positive relationship between metabolic flexibility and
insulin sensitivity [183]. Expression of SCD (stearoylCoA desaturase) 1, which catalyses the synthesis of
monounsaturated FAs, is enhanced in skeletal muscle
from obese humans [184]. High expression and activity
of SCD1 correlates with low rates of FA oxidation
and increased TAG synthesis, together with increased
relative abundance of monounsaturated compared with
saturated FAs. Importantly, elevated SCD1 expression
and abnormal lipid partitioning are retained in primary
skeletal myocytes derived from obese compared with lean
donors, implying that these traits might be driven by epigenetic and/or heritable mechanisms. Overexpression of
human SCD1 in myotubes from lean subjects reproduces
the obese phenotype.
Although glucose and fructose share the same empirical formula, their metabolism is quite different. Fructose
is unable to stimulate insulin secretion in the absence of
stimulatory glucose concentration [185], and has a low
glycaemic index. A potential association between increased fructose consumption and the prevalence of
obesity, insulin resistance and Type 2 diabetes has been
highlighted (reviewed in [186]). Dietary fructose is converted into fructose 1-phosphate by fructokinase, abundantly expressed in liver, the organ primarily responsible
for extraction of absorbed fructose (reviewed in
[186,187]). Fructokinase activity in the liver is usually
higher than glucokinase and hexokinase activities combined and, whereas glucose metabolism is negatively
regulated by PFK1, fructose by-passes this critical
regulatory step, thereby serving as an unregulated hepatic
acetyl-CoA generator (reviewed in [186,187]). Fructosederived acetyl-CoA serves as a precursor for FA synthesis. Fructose can also provide carbon for glycerol 3phosphate synthesis. Glycerol 3-phosphate and FAs are
used to form hepatic TAG, thereby facilitating high rates
of hepatic VLDL (very-low-density lipoprotein) production. An increase in lipoprotein assembly, enhanced
expression of hepatic microsomal TAG protein and reduced Apo (apolipoprotein) B degradation are observed
on ingestion of a high-fructose diet [188]. Fructose
also lowers the ApoE to ApoC ratio, thereby reducing
VLDL-TAG removal by peripheral tissues [189]. As a
consequence, fructose often induces hypertriglyceridaemia in the postprandial state. Chronic hyperinsulin-
aemia and increased plasma FAs, commonly seen with
insulin resistance and central obesity, exacerbate this
action.
Diets high in fructose induce systemic insulin resistance, with reduced tyrosine phosphorylation of the
insulin receptor and IRS1 ([190]; reviewed in [174]).
Normal weight and/or insulin-sensitive subjects may
be relatively resistant to the insulin-desensitizing effect
of sustained fructose, whereas fructose may be more
likely to exacerbate insulin resistance in subjects where
insulin action is already impaired, as in obesity [186].
However, the addition of relatively modest amounts of
fructose to the diet may have beneficial effects on glucose
handling by subjects with Type 2 diabetes during periods
of neutral energy balance (see e.g. [191,192]), possibly
because of improved hepatic glucose uptake through
hepatic glucokinase activation [193].
Fructose consumption attenuates postprandial suppression of ghrelin [194] and, in this way, high dietary
fructose may contribute to the accelerated rates of obesity in modern societies [186]. Different mouse strains
have differing susceptibilities to the metabolic derangements induced by high-fructose diets (reviewed in
[187]), indicating a genetic component. Postprandial
hyperinsulinaemia, hypertriglyceridaemia and visceral fat
accumulation following the ingestion of a high-fructose
diet can be associated with increased hepatic expression
of SREBP1, and susceptibility to metabolic perturbations
following a high-fructose diet may be determined by
polymorphisms in the SREBP1 gene [187]. In mice lacking SCD, a 60 % fructose diet failed to induce SREBP1
and lipogenic gene expression ([195]; reviewed in [187]).
Conversely, mice deficient in the FA transport protein CD36 are more responsive to fructose-induced
impairments in insulin action than wild-type mice [196].
Dietary lipid and consequences
of its excess
Dietary lipid is presented mainly in the form of TAG,
with some NEFAs, cholesterol and sterols. Lipids enter
the blood stream as chylomicrons. LPLs, located on the
luminal surface of capillary endothelial cells, hydrolyse the TAG component to FA and monoacylglycerol.
NEFAs then enter cells or bind to albumin for distribution in the circulation [53]. Mice lacking CD36
exhibit decreased FA uptake in muscle (cardiac and
skeletal) and adipose tissue [197]; decreasing FA uptake
into skeletal muscle improves insulin sensitivity [198].
Similarly, FATP1-knockout mice are resistant to lipidinduced insulin resistance in muscle [199]. In adipocytes,
translocation of FATP1 from the intracellular perinuclear
compartment to the plasma membrane is induced by insulin, and this coincides with increased adipose-tissue FA
uptake [200]. Thus the uptake of FAs in adipose tissue
is regulated by insulin via FATP1 and, as a consequence,
C
2007 The Biochemical Society
103
104
C. G. Walker and others
FATP1-null mice are protected against obesity induced
by the provision of a high-saturated-fat diet [200]. Within
cells, FAs are sequestered by tissue-specific binding
proteins [FABPs (FA-binding proteins), also known
as LBPs (lipid-binding proteins)]. Adipocytes contain ALBP (adipocyte LBP) and KLBP (keranocyte
LBP). ALBP complexes with HSL and may sequester FAs
as they are released by lipolysis [201]. Compared with
wild-type controls, ALBP-null mice exhibit decreased
FA release from adipose tissue, increased epididymal
fat mass and increased glucose oxidation relative to fat
oxidation in the fasting state [202]. Mice deficient in the
perilipin (which coats the lipid droplet and which, when
phosphorylated, facilitates translocation of HSL to the
surface of the lipid droplet) have a reduced adipose-tissue
mass and resistance to diet-induced and genetic obesity
[203].
Some controversy exists over the quantity and type of
dietary fats involved in the development of insulin
resistance, obesity and diabetes [204]. The specific type of
dietary fat, rather than the amount, appears to be more
significant [205]. Thus despite a reduction in dietary fat
as a percentage of energy intake in developed countries
such as U.S., there has nevertheless been a dramatic rise
in the prevalence of obesity and Type 2 diabetes. The
consensus view is that diets high in saturated fats favour
the development of insulin resistance and, in susceptible
individuals, obesity. In rats, diets high in saturated fats
or rich in linoleic acid (an n−6 FA) lead to insulin resistance [206] and inhibit liver and muscle PI3K activity
[207]. In adipose tissue, this is associated with decreased
GLUT4 expression and PI3K activity [208]. Conversely,
consumption of diets rich in polyunsaturated and
monounsaturated FAs improve insulin sensitivity, as well
as having a beneficial effect on obesity [209]. The role
of FAs, particularly polyunsaturated FAs of the n−6 and
n−3 series, as regulators of adipogenesis and in relation
to the development of obesity has been reviewed recently
[210].
Only moderate modification of the type of FAs
included in the diet is necessary to prevent adverse effects
of dietary fat on insulin action. The substitution of n−3
long-chain FAs [mainly EPA (eicosapentaenoic acid) and
DPA (docosahexaenoic acid)] for only a small percentage
(6–7 %) of saturated FAs prevents the development of
whole-body insulin resistance elicited in response to
high-saturated-fat feeding [206,211]. Furthermore, when
fish oil, rich in long-chain n−3 FA is substituted for onethird of the lipid fraction of the diet, the decrease in
muscle PI3K activity is completely prevented, as is decreased adipose-tissue SLC2A4 (GLUT4) gene expression [207]. However, suppression of hepatic PI3K
activity remains unaffected [207]. Long-chain n−3 FA
enrichment of a high-saturated-fat diet leads to hepatic
insulin resistance with respect to suppression of glucose
output despite improved peripheral insulin sensiti
C
2007 The Biochemical Society
vity [211]. Thus n−3 FAs influence insulin signalling
introduced by high-saturated fat in a tissue-specific
manner. Supplementation of a low-fat diet with a low level
of long-chain n−3 FA increases PI3K activity in adipose
tissue [208]. It was suggested that this enhancement
of PI3K activity, if accompanied by increased glucose
uptake, could compensate for impaired insulin signalling
in other tissues, including liver [208].
Polyunsaturated FAs are more potent activators of
PPARα than saturated FA or monounsaturated FAs
[212]; nevertheless, PPARα is activated during chronic
high-saturated-fat feeding and mediates the effect of highsaturated-fat feeding on hepatic gene expression [213].
In PPARα-null mice, the effect of high-fat feeding
on PPARα target genes in liver may be mediated by
PPARγ , which is up-regulated, as PPARγ does not
appear to possess any intrinsic property that prevents it
from activating classical PPARα target genes [213]. Upregulation of hepatic PPARα expression in response to
high-saturated-fat feeding in C57BL/6 mice occurs only
in those developing obesity, but not in those remaining
lean [214]. Thus, as for fructose, there may be genetic
(or epigenetic) predisposition to become insulin resistant
in response to dietary lipid. Indeed, there is considerable
variability between individuals in their abilities to respond to increased dietary lipid; some individuals increase
FA oxidation, others (for example those with obesity or a
family history of obesity) do not, and instead accumulate
intracellular lipid [215].
Involvement of lipid derivatives in insulin
resistance induced by diets high in lipids
or fructose
Parallels exist between the effects of fructose- and lipidenriched diets to induce insulin resistance, as both
may be due to increased lipid delivery to insulin-sensitive tissues. Many studies have shown an association
between tissue insulin resistance and intracellular lipid
accumulation in high-fat-fed animals [216,217]. Intramuscular TAG content correlates more closely with systemic insulin resistance than BMI or total adiposity
[217]. Candidate mediators of insulin resistance include
ceramide (a lipotoxic derivative of FAs), lipid metabolites
involved in the synthesis of TAG (e.g. FA-CoA) or
generated by TAG hydrolysis (e.g. DAG). These lipid
metabolites can alter insulin action by impairing tyrosine
phosphorylation of the insulin receptor and IRS1 (reviewed in [218,219]). FAs can activate a serine kinase
cascade, culminating in serine phosphorylation of IRS1
at Ser307 , leading to decreased IRS1 tyrosine phosphorylation and IRS1-associated PI3K activity, and inhibition
of downstream components of the insulin signalling
pathway, such as PKB (protein kinase B)/Akt [220].
Ceramide also impairs activation of IRS1, PI3K and
PKB/Akt [221,222]. This mechanism appears to depend
Diet, obesity and diabetes
on the type of FA, and is inoperative when muscle is
exposed to mono- or poly-unsaturated FAs [223]. More
generally, the FA signalling cascade may also involve
IKK (inhibitor of κB kinase) [216] and/or persistent
translocation and activation of DAG-sensitive isoforms
of PKC (protein kinase C). Inhibition of these kinases
by pharmacological or genetic means can reverse insulin
resistance in rodents (e.g [224]). Insulin resistance induced
by diets high in either fructose or saturated fat is also
ameliorated by lowering of circulating lipids and dissipation of tissue lipids by, for example, low-fat feeding,
fasting and exercise or PPARα activation [225–228].
AMPK phosphorylates and inactivates ACC, and FA
oxidation consequently rises through relief of malonylCoA-induced suppression of CPT1 activity. AMPK
would therefore be predicted to relieve insulin resistance
secondary to lipid accumulation. Dietary polyunsaturated FAs have been shown to enhance hepatic AMPK
activity [229]. Interestingly, both leptin and adiponectin
activate AMPK [230]. Mice lacking the α2 subunit display
increased insulin sensitivity [231,232], whereas the α3
isoform has been suggested to have a role in the regulation
of carbohydrate metabolism in muscle (reviewed in
[233]). Transgenic mice overexpressing a mutant (TgPrkag3225Q ) form of AMPK, AMPKγ 3, which increases
ACC phosphorylation, are protected against insulin
resistance induced by high-fat feeding [234]. Clearly,
AMPK dysregulation has a significant association with
obesity and Type 2 diabetes.
CONCLUSIONS AND NEW DIRECTIONS
Obesity is increasing rapidly in prevalence, but the effects
of obesity on the regulation of energy balance is only now
being recognized fully. Emerging research has revealed
that adipose-tissue function and adipose-tissue factors
play an important role in the control of energy balance.
The massive expansion of adipose tissue that accompanies
obesity is associated with a loss of normal regulation
of adipose-tissue function and adipokine secretion. Many
adipokines are regulated by nutritional factors which are
also altered by the development of insulin resistance and
diabetes. The alterations to adipose-tissue function and
adipokine regulation can, in turn, alter the regulation of
energy balance.
Extending the lipostatic hypothesis for hypothalamic
nutrient sensing, an exciting new finding is that restoration of hypothalamic lipid-sensing normalizes energy
and glucose homoeostasis in Sprague–Dawley rats presented with a high-palatable lard-supplemented diet
[235]. These overfed rats fail to respond either to the
systemic administration of leptin [236] or to the central
administration of oleic acid [237]. Overfed rats failed to
respond to doubling of concentrations of long-chain FAs
in the circulation with doubling of concentrations of
long-chain FAs in the MBH (mediobasal hypothalamus),
due to decreased MBH malonyl-CoA concentrations
[235]. Inhibition of MBH CPT1 activity by infusing a
sequence-specific ribozyme against CPT1A or an isoform-selective inhibitor of CPT1 normalized hypothalamic levels of long-chain CoA and markedly inhibited
feeding behaviour despite leptin resistance [235]. Thus
MBH levels of long-chain FAs may act downstream of
leptin signalling, perhaps directly at the level of AMPK.
Importantly, this manipulation also normalized the
excessive hepatic glucose output observed in the overfed
animals [235]. These new studies indicate that improved
nutrient sensing may hold the key for improving insulin
resistance in obesity and Type 2 diabetes.
ACKNOWLEDGMENTS
We thank Diabetes UK and the British Heart Foundation
for supporting our research. M. G. Z. is the recipient of a
Diabetes UK Studentship.
REFERENCES
1 Druce, M. and Bloom, S. R. (2006) The regulation of
appetite. Arch. Dis. Child. 91, 183–187
2 Bray, G. A. (2004) Medical consequences of obesity.
J. Clin. Endocrinol. Metab. 89, 2583–2589
3 Caterson, I. D., Hubbard, V., Bray, G. A. et al. (2004)
Prevention Conference VII: obesity, a worldwide
epidemic related to heart disease and stroke: Group III:
worldwide co-morbidities of obesity. Circulation 110,
e476–e484
4 Kopelman, P. G. (2000) Obesity as a medical problem.
Nature 404, 635–643
5 Stumvoll, M., Goldstein, B. J. and van Haeften, T. W.
(2005) Type 2 diabetes: principles of pathogenesis and
therapy. Lancet 365, 1333–1346
6 Smyth, S. and Heron, A. (2005) Diabetes and obesity:
the twin epidemics. Nat. Med. 12, 75–80
7 Miller, J., Rosenbloom, A. and Silverstein, J. (2004)
Childhood obesity. J. Clin. Endocrinol. Metab. 89,
4211–4218
8 Swinburn, B. A., Caterson, I. D., Seidell, J. C. and James,
W. P. (2004) Diet, nutrition and the prevention of excess
weight gain and obesity. Public Health Nutr. 1A, 123–146
9 Caterson, I. D. and Gill, T. P. (2002) Obesity:
epidemiology and possible prevention. Best Pract. Res.
Clin. Endocrinol. Metab. 16, 595–610
10 Flier, J. S. and Maratos-Flier, E. (1998) Obesity and the
hypothalamus: novel peptides for new pathways. Cell 92,
437–440
11 Lev-Ran, A. (2001) Human obesity: an evolutionary
approach to understanding our bulging waistline.
Diabetes Metab. Res. Rev. 17, 347–362
12 Ravussin, E. (2002) Cellular sensors of feast and famine.
J. Clin. Invest. 109, 1537–1540
13 Hales, C. N. and Barker, D. J. (1992) Type 2 (noninsulin-dependent) diabetes mellitus: the thrifty
phenotype hypothesis. Diabetologia 35, 595–601
14 Holness, M. J., Langdown, M. L. and Sugden, M. C.
(2000) Early-life programming of susceptibility to
dysregulation of glucose metabolism and the development
of Type 2 diabetes mellitus. Biochem. J. 349, 657–665
15 Stocker, C. J., Arch, J. R. and Cawthorne, M. A. (2005)
Fetal origins of insulin resistance and obesity.
Proc. Nutr. Soc. 64, 143–151
16 Holness, M. J. and Sugden, M. C. (2006) Epigenetic
regulation of metabolism in children born small for
gestational age. Curr. Opin. Clin. Nutr. Metab. Care 9,
482–488
C
2007 The Biochemical Society
105
106
C. G. Walker and others
17 Martin-Gronert, M. S. and Ozanne, S. E. (2005)
Programming of appetite and type 2 diabetes.
Early Hum. Dev. 81, 981–988
18 Fruhbeck, G., Gomez-Ambrosi, J., Muruzabal, F. J.
and Burrell, M. A. (2001) The adipocyte: a model for
integration of endocrine and metabolic signaling in energy
metabolism regulation. Am. J. Physiol. Endocrinol.
Metab. 280, E827–E847
19 Guan, H. P., Li, Y., Jensen, M. V., Newgard, C. B.,
Steppan, C. M. and Lazar, M. A. (2002) A futile metabolic
cycle activated in adipocytes by antidiabetic agents.
Nat. Med. 8, 1122–1128
20 Picard, F. and Auwerx, J. (2002) PPARγ and glucose
homeostasis. Annu. Rev. Nutr. 22, 167–197
21 Tordjman, J., Khazen, W., Antoine, B. et al. (2003)
Regulation of glyceroneogenesis and
phosphoenolpyruvate carboxykinase by fatty acids,
retinoic acids and thiazolidinediones: potential relevance
to type 2 diabetes. Biochimie 85, 1213–1218
22 Gray, S. L., Dalla, N. E. and Vidal-Puig, A. J. (2005)
Mouse models of PPAR-γ deficiency: dissecting
PPAR-γ ’s role in metabolic homoeostasis.
Biochem. Soc. Trans. 33, 1053–1058
23 Rangwala, S. M. and Lazar, M. A. (2004) Peroxisome
proliferator-activated receptor γ in diabetes and
metabolism. Trends Pharmacol. Sci. 25, 331–336
24 Semple, R. K., Chatterjee, V. K. K. and O’Rahilly, S.
(2006) PPARγ and human metabolic disease.
J. Clin. Invest. 116, 581–589
25 Petersen, K. F. and Shulman, G. I. (2006) Etiology of
insulin resistance. Am. J. Med. 119, S10–S16
26 Franckhauser, S., Munoz, S., Elias, I., Ferre, T. and
Bosch, F. (2006) Adipose overexpression of
phosphoenolpyruvate carboxykinase leads to high
susceptibility to diet-induced insulin resistance and
obesity. Diabetes 55, 273–280
27 Coppack, S. W., Evans, R. D., Fisher, R. M. et al. (1992)
Adipose tissue metabolism in obesity: lipase action
in vivo before and after a mixed meal. Metab., Clin. Exp.
41, 264–272
28 Horowitz, J. F., Coppack, S. W., Paramore, D., Cryer,
P. E., Zhao, G. and Klein, S. (1999) Effect of short-term
fasting on lipid kinetics in lean and obese women.
Am. J. Physiol. 276, E278–E284
29 Armoni, M., Harel, C., Burvin, R. and Karnieli, E. (1995)
Modulation of the activity of glucose transporters
(GLUT) in the aged/obese rat adipocyte: suppressed
function, but enhanced intrinsic activity of GLUT.
Endocrinology 136, 3292–3298
30 Weyer, C., Foley, J. E., Bogardus, C., Tataranni, P. A. and
Pratley, R. E. (2000) Enlarged subcutaneous abdominal
adipocyte size, but not obesity itself, predicts type II
diabetes independent of insulin resistance. Diabetologia
43, 1498–1506
31 Unger, R. H. and Zhou, Y. T. (2001) Lipotoxicity of
β-cells in obesity and in other causes of fatty acid
spillover. Diabetes 50 (Suppl. 1), S118–S121
32 Frayn, K. N. (2005) Obesity and metabolic disease: is
adipose tissue the culprit? Proc. Nutr. Soc. 64,
7–13
33 El-Assaad, W., Buteau, J., Peyot, M. L. et al. (2003)
Saturated fatty acids synergize with elevated glucose to
cause pancreatic β-cell death. Endocrinology 144,
4154–4163
34 Bluher, M., Michael, M. D., Peroni, O. D. et al. (2002)
Adipose tissue selective insulin receptor knockout
protects against obesity and obesity-related glucose
intolerance. Dev. Cell 3, 25–38
35 Ahima, R. S. and Flier, J. S. (2000) Adipose tissue as an
endocrine organ. Trends Endocrinol. Metab. 11,
327–332
36 Kershaw, E. E. and Flier, J. S. (2004) Adipose tissue as an
endocrine organ. J. Clin. Endocrinol. Metab. 89,
2548–2556
37 Liu, Y. M., Moldes, M., Bastard, J. P. et al. (2004)
Adiponutrin: a new gene regulated by energy balance in
human adipose tissue. J. Clin. Endocrinol. Metab. 89,
2684–2689
C
2007 The Biochemical Society
38 Kershaw, E. E., Hamm, J. K., Verhagen, L. A., Peroni, O.,
Katic, M. and Flier, J. S. (2006) Adipose triglyceride
lipase: function, regulation by insulin, and comparison
with adiponutrin. Diabetes 55, 148–157
39 Zechner, R., Strauss, J. G., Haemmerle, G., Lass, A. and
Zimmermann, R. (2005) Lipolysis: pathway under
construction. Curr. Opin. Lipidol. 16, 333–340
40 Lass, A., Zimmermann, R., Haemmerle, G. et al. (2006)
Adipose triglyceride lipase-mediated lipolysis of cellular
fat stores is activated by CGI-58 and defective in
Chanarin–Dorfman syndrome. Cell Metab. 3, 309–319
41 Mairal, A., Langin, D., Arner, P. and Hoffstedt, J. (2006)
Human adipose triglyceride lipase (PNPLA2) is not
regulated by obesity and exhibits low in vitro triglyceride
hydrolase activity. Diabetologia 49, 1629–1636
42 Langin, D., Dicker, A., Tavernier, G. et al. (2005)
Adipocyte lipases and defect of lipolysis in human
obesity. Diabetes 54, 3190–3197
43 Ferre, P. (2004) The biology of peroxisome proliferatoractivated receptors: relationship with lipid metabolism
and insulin sensitivity. Diabetes 53, S43–S50
44 Kersten, S., Seydoux, J., Peters, J. M., Gonzalez, F. J.,
Desvergne, B. and Wahli, W. (1999) Peroxisome
proliferator-activated receptor α mediates the adaptive
response to fasting. J. Clin. Invest. 103, 1489–1498
45 Sugden, M. C., Bulmer, K., Gibbons, G. F., Knight, B. L.
and Holness, M. J. (2002) Peroxisome-proliferatoractivated receptor-α (PPARα) deficiency leads to
dysregulation of hepatic lipid and carbohydrate
metabolism by fatty acids and insulin. Biochem. J. 364,
361–368
46 Patsouris, D., Mandard, S., Voshol, P. J. et al. (2004)
PPARα governs glycerol metabolism. J. Clin. Invest 114,
94–103
47 Hibuse, T., Maeda, N., Funahashi, T. et al. (2005)
Aquaporin 7 deficiency is associated with development of
obesity through activation of adipose glycerol kinase.
Proc. Natl. Acad. Sci. U.S.A 102, 10993–10998
48 Hara-Chikuma, M., Sohara, E., Rai, T. et al. (2005)
Progressive adipocyte hypertrophy in aquaporin-7deficient mice: adipocyte glycerol permeability as a novel
regulator of fat accumulation. J. Biol. Chem. 280,
15493–15496
49 Kishida, K., Shimomura, I., Kondo, H. et al. (2001)
Genomic structure and insulin-mediated repression of the
aquaporin adipose (AQPap), adipose-specific glycerol
channel. J. Biol. Chem. 276, 36251–36260
50 Kondo, H., Shimomura, I., Kishida, K. et al. (2002)
Human aquaporin adipose (AQPap) gene. Genomic
structure, promoter analysis and functional mutation.
Eur. J. Biochem. 269, 1814–1826
51 Prins, J. B. (2002) Adipose tissue as an endocrine organ.
Best Pract. Res. Clin. Endocrinol. Metab. 16, 639–651
52 Bosello, O. and Zamboni, M. (2000) Visceral obesity and
metabolic syndrome. Obes. Rev. 1, 47–56
53 Frayn, K. N., Fielding, B. A. and Karpe, F. (2005) Adipose
tissue fatty acid metabolism and cardiovascular disease.
Curr. Opin. Lipidol. 16, 409–415
54 Wong, S., Huda, M., English, P. et al. (2005) Adipokines
and the insulin resistance syndrome in familial partial
lipodystrophy caused by a mutation in lamin A/C.
Diabetologia 48, 2641–2649
55 Shimomura, I., Hammer, R., Ikemoto, S., Brown, M. and
Goldstein, J. (1999) Leptin reverses insulin resistance
and diabetes mellitus in mice with congenital
lipodystrophy. Nature 401, 73–76
56 Hillebrand, J. J., de Wied, D. and Adan, R. A. (2002)
Neuropeptides, food intake and body weight regulation:
a hypothalamic focus. Peptides 23, 2283–2306
57 Coleman, D. L. (1978) Obese and diabetes: two mutant
genes causing diabetes-obesity syndromes in mice.
Diabetologia 14, 141–148
58 Wang, M. Y., Lee, Y. and Unger, R. H. (1999) Novel form
of lipolysis induced by leptin. J. Biol. Chem. 274,
17541–17544
59 Kim, J. K., Gavrilova, O., Chen, Y., Reitman, M. L. and
Shulman, G. I. (2000) Mechanism of insulin resistance in
A-ZIP/F-1 fatless mice. J.Biol. Chem. 275, 8456–8460
Diet, obesity and diabetes
60 Colombo, C., Cutson, J. J., Yamauchi, T. et al. (2002)
Transplantation of adipose tissue lacking leptin is unable
to reverse the metabolic abnormalities associated with
lipoatrophy. Diabetes 51, 2727–2733
61 Ahren, B., Mansson, S., Gingerich, R. L. and Havel, P. J.
(1997) Regulation of plasma leptin in mice: influence of
age, high-fat diet, and fasting. Am. J. Physiol. 273,
R113–R120
62 Banerji, M. A., Faridi, N., Atluri, R., Chaiken, R. L. and
Lebovitz, H. E. (1999) Body composition, visceral fat,
leptin, and insulin resistance in Asian Indian men. J. Clin.
Endocrinol. Metab. 84, 137–144
63 Havel, P. J., Townsend, R., Chaump, L. and Teff, K.
(1999) High-fat meals reduce 24-h circulating leptin
concentrations in women. Diabetes 48, 334–341
64 Maffei, M., Halaas, J., Ravussin, E. et al. (1995) Leptin
levels in human and rodent: measurement of plasma leptin
and ob RNA in obese and weight-reduced subjects.
Nat. Med. 1, 1155–1161
65 Schwartz, M. W., Peskind, E., Raskind, M., Boyko, E. J.
and Porte, Jr, D. (1996) Cerebrospinal fluid leptin levels:
relationship to plasma levels and to adiposity in humans.
Nat. Med. 2, 589–593
66 Walker, C. G., Bryson, J. M., Phuyal, J. L. and Caterson,
I. D. (2002) Dietary modulation of circulating leptin
levels: site-specific changes in fat deposition and ob
mRNA expression. Horm. Metab. Res. 34, 176–181
67 Walker, C. G., Bryson, J. M., Bell-Anderson, K. S.,
Hancock, D. P., Denyer, G. S. and Caterson, I. D. (2005)
Insulin determines leptin responses during a glucose
challenge in fed and fasted rats. Int. J. Obes. 29, 398–405
68 Levy, J. R., Gyarmati, J., Lesko, J. M., Adler, R. A. and
Stevens, W. (2000) Dual regulation of leptin secretion:
intracellular energy and calcium dependence of regulated
pathway. Am. J. Physiol. Endocrinol. Metab. 278,
E892–E901
69 Mizuno, T. M., Bergen, H., Funabashi, T. et al. (1996)
Obese gene expression: reduction by fasting and
stimulation by insulin and glucose in lean mice,
and persistent elevation in acquired (diet-induced) and
genetic (yellow agouti) obesity. Proc. Natl. Acad.
Sci. U.S.A. 93, 3434–3438
70 Saladin, R., De Vos, P., Guerre-Millo, M. et al. (1995)
Transient increase in obese gene expression after food
intake or insulin administration. Nature 377, 527–529
71 Bradley, R. L. and Cheatham, B. (1999) Regulation of ob
gene expression and leptin secretion by insulin and
dexamethasone in rat adipocytes. Diabetes 48, 272–278
72 Mueller, W. M., Gregoire, F. M., Stanhope, K. L. et al.
(1998) Evidence that glucose metabolism regulates leptin
secretion from cultured rat adipocytes. Endocrinology
139, 551–558
73 Cammisotto, P. G., Gelinas, Y., Deshaies, Y. and
Bukowiecki, L. J. (2003) Regulation of leptin secretion
from white adipocytes by free fatty acids. Am. J. Physiol
Endocrinol. Metab. 285, E521–E526
74 Shintani, M., Nishimura, H., Yonemitsu, S. et al. (2000)
Downregulation of leptin by free fatty acids in rat
adipocytes: effects of triacsin C, palmitate, and
2-bromopalmitate. Metab., Clin. Exp. 49, 326–330
75 Donahoo, W. T., Jensen, D. R., Yost, T. J. and Eckel, R. H.
(1997) Isoproterenol and somatostatin decrease plasma
leptin in humans: a novel mechanism regulating leptin
secretion. J. Clin. Endocrinol. Metab. 82, 4139–4143
76 Coppack, S. W., Pinkney, J. H. and Mohamed-Ali, V.
(1998) Leptin production in human adipose tissue.
Proc. Nutr. Soc. 57, 461–470
77 Hardie, L. J., Rayner, D. V., Holmes, S. and Trayhurn, P.
(1996) Circulating leptin levels are modulated by fasting,
cold exposure and insulin administration in lean but not
Zucker (fa/fa) rats as measured by ELISA.
Biochem. Biophys. Res. Commun. 223, 660–665
78 Wang-Fisher, Y. L., Han, J. and Guo, W. (2002) Acipimox
stimulates leptin production from isolated rat adipocytes.
Endocrinology 174, 267–272
79 Berndt, J., Kloting, N., Kralisch, S. et al. (2005) Plasma
visfatin concentrations and fat depot-specific mRNA
expression in humans. Diabetes 54, 2911–2916
80 Kloting, N. and Kloting, I. (2005) Visfatin: gene
expression in isolated adipocytes and sequence
analysis in obese WOKW rats compared with lean
control rats. Biochem. Biophys. Res. Commun. 332,
1070–1072
81 Fukuhara, A., Matsuda, M., Nishizawa, M. et al. (2005)
Visfatin: a protein secreted by visceral fat that mimics the
effects of insulin. Science 307, 426–430
82 Chen, M. P., Chung, F. M., Chang, D. M. et al. (2006)
Elevated plasma level of visfatin/pre-B cell colonyenhancing factor in patients with type 2 diabetes mellitus.
J. Clin. Endocrinol. Metab. 91, 295–299
83 Krzyzanowska, K., Krugluger, W., Mittermayer, F. et al.
(2006) Increased visfatin concentrations in women with
gestational diabetes mellitus. Clin. Sci. 110, 605–609
84 Murphy, K. G. and Bloom, S. R. (2006) Are all fats created
equal? Nat. Med. 12, 32–33
85 Berg, A. H., Combs, T. P., Du, X., Brownlee, M. and
Scherer, P. E. (2001) The adipocyte-secreted protein
Acrp30 enhances hepatic insulin action. Nat. Med. 7,
947–953
86 Yamauchi, T., Kamon, J., Waki, H. et al. (2001) The
fat-derived hormone adiponectin reverses insulin
resistance associated with both lipoatrophy and obesity.
Nat. Med. 7, 941–946
87 Maeda, N., Shimomura, I., Kishida, K. et al. (2002)
Diet-induced insulin resistance in mice lacking
adiponectin/ACRP30. Nat. Med. 8, 731–737
88 Okamoto, Y., Kihara, S., Funahashi, T., Matsuzawa, Y.
and Libby, P. (2006) Adiponectin: a key adipocytokine in
metabolic syndrome. Clin. Sci. 110, 267–278
89 Hu, E., Liang, P. and Spiegelman, B. M. (1996) AdipoQ is
a novel adipose-specific gene dysregulated in obesity.
J. Biol. Chem. 271, 10697–10703
90 Fasshauer, M., Klein, J., Neumann, S., Eszlinger, M. and
Paschke, R. (2002) Hormonal regulation of adiponectin
gene expression in 3T3-L1 adipocytes. Biochem. Biophys.
Res. Commun. 290, 1084–1089
91 Kita, A., Yamasaki, H., Kuwahara, H. et al. (2005)
Identification of the promoter region required for human
adiponectin gene transcription: association with
CCAAT/enhancer binding protein-β and tumor necrosis
factor-α. Biochem. Biophys. Res. Commun. 331,
484–490
92 Trayhurn, P. and Wood, I. S. (2005) Signalling role of
adipose tissue: adipokines and inflammation in obesity.
Biochem. Soc. Trans. 33, 1078–1081
93 Trayhurn, P. (2005) Adipose tissue in obesity: an
inflammatory issue. Endocrinology 146, 1003–1005
94 Furukawa, S., Fujita, T., Shimabukuro, M. et al. (2004)
Increased oxidative stress in obesity and its impact on
metabolic syndrome. J. Clin. Invest. 114, 1752–1761
95 O’Doherty, R. M. and Nguyen, L. (2004) Blunted
fasting-induced decreases in plasma and CSF leptin
concentrations in obese rats: the role of increased leptin
secretion. Int. J. Obes. Relat. Metab. Disord. 28,
173–175
96 Fruehwald-Schultes, B., Oltmanns, K. M., Kern, W.,
Born, J., Fehm, H. L. and Peters, A. (2002) The effect of
experimentally induced insulin resistance on the leptin
response to hyperinsulinaemia. Int. J. Obes.
Relat. Metab. Disord. 26, 510–516
97 Holness, M. J. and Sugden, M. C. (2001) Antecedent
protein restriction and high-fat feeding interactively
sensitise the leptin response to elevated insulin.
Mol. Cell. Endocrinol. 173, 53–62
98 Pagano, C., Englaro, P., Granzotto, M. et al. (1997)
Insulin induces rapid changes of plasma leptin in lean but
not in genetically obese (fa/fa) rats. Int. J. Obes. Relat.
Metab. Disord. 21, 614–618
99 English, P. J., Coughlin, S. R., Hayden, K., Malik, I. A.
and Wilding, J. P. H. (2003) Plasma adiponectin increases
postprandially in obese, but not in lean, subjects.
Obes. Res. 11, 839–844
100 Yu, J. G., Javorschi, S., Hevener, A. L. et al. (2002) The
effect of thiazolidinediones on plasma adiponectin levels
in normal, obese, and Type 2 diabetic subjects. Diabetes
51, 2968–2974
C
2007 The Biochemical Society
107
108
C. G. Walker and others
101 Zhang, Y., Proenca, R., Maffei, M., Barone, M.,
Leopold, L. and Friedman, J. M. (1994) Positional cloning
of the mouse obese gene and its human homologue.
Nature 372, 425–432
102 Friedman, J. M. and Halaas, J. L. (1998) Leptin and the
regulation of body weight in mammals. Nature 395,
763–770
103 Sahu, A. (2003) Leptin signaling in the hypothalamus:
emphasis on energy homeostasis and leptin resistance.
Front. Neuroendocrinol. 24, 225–253
104 Schwartz, M. W., Woods, S. C., Porte, Jr, D., Seeley, R. J.
and Baskin, D. G. (2000) Central nervous system control
of food intake. Nature 404, 661–671
105 Erickson, J. C., Hollopeter, G. and Palmiter, R. D. (1996)
Attenuation of the obesity syndrome of ob/ob mice by
the loss of neuropeptide Y. Science 274, 1704–1707
106 Stephens, T. W., Basinski, M., Bristow, P. K. et al. (1995)
The role of neuropeptide Y in the antiobesity action of
the obese gene product. Nature 377, 530–532
107 Hewson, A. K., Tung, L. Y., Connell, D. W., Tookman, L.
and Dickson, S. L. (2002) The rat arcuate nucleus
integrates peripheral signals provided by leptin, insulin,
and a ghrelin mimetic. Diabetes 51, 3412–3419
108 Billington, C. J., Briggs, J. E., Grace, M. and Levine, A. S.
(1991) Effects of intracerebroventricular injection of
neuropeptide Y on energy metabolism. Am. J. Physiol.
260, R321–R327
109 Segal-Lieberman, G., Bradley, R. L., Kokkotou, E. et al.
(2003) Melanin-concentrating hormone is a critical
mediator of the leptin-deficient phenotype. Proc. Natl.
Acad. Sci. U.S.A. 100, 10085–10090
110 Stanley, B. G., Kyrkouli, S. E., Lampert, S. and Leibowitz,
S. F. (1986) Neuropeptide Y chronically injected into the
hypothalamus: a powerful neurochemical inducer of
hyperphagia and obesity. Peptides 7, 1189–1192
111 Marks, D. L., Boucher, N., Lanouette, C. M. et al. (2004)
Ala67Thr polymorphism in the Agouti-related peptide
gene is associated with inherited leanness in humans.
Am. J. Med. Genet. A 126, 267–271
112 Savontaus, E., Conwell, I. M. and Wardlaw, S. L. (2002)
Effects of adrenalectomy on AGRP, POMC, NPY and
CART gene expression in the basal hypothalamus of fed
and fasted rats. Brain Res. 958, 130–138
113 Bertile, F., Oudart, H., Maho, Y. L. and Raclot, T. (2003)
Recombinant leptin in the hypothalamic response to late
fasting. Biochem. Biophys. Res. Commun. 310, 949–955
114 Farooqi, I. S. and O’Rahilly, S. (2005) New advances in
the genetics of early onset obesity. Int. J. Obes. Relat.
Metab. Disord. 29, 1149–1152
115 Lam, T. K. T., Gutierrez-Juarez, R., Pocai, A. and
Rossetti, L. (2005) Regulation of blood glucose by
hypothalamic pyruvate metabolism. Science 309,
943–947
116 Anderson, G. H., Catherine, N. L., Woodend, D. M. and
Wolever, T. M. (2002) Inverse association between the
effect of carbohydrates on blood glucose and subsequent
short-term food intake in young men. Am. J. Clin. Nutr.
76, 1023–1030
117 Lam, T. K., Schwartz, G. J. and Rossetti, L. (2005)
Hypothalamic sensing of fatty acids. Nat. Neurosci. 8,
579–584
118 Obici, S., Feng, Z., Morgan, K., Stein, D., Karkanias, G.
and Rossetti, L. (2002) Central administration of oleic
acid inhibits glucose production and food intake.
Diabetes 51, 271–275
119 McGarry, J. D. and Dobbins, R. L. (1999) Fatty acids,
lipotoxicity and insulin secretion. Diabetologia 42,
128–138
120 Randle, P. J. (1998) Regulatory interactions between lipids
and carbohydrates: the glucose fatty acid cycle after 35
years. Diabetes Metab. Rev. 14, 263–283
121 McGarry, J. D., Mannaerts, G. P. and Foster, D. W. (1977)
A possible role for malonyl-CoA in the regulation of
hepatic fatty acid oxidation and ketogenesis.
J. Clin. Invest. 60, 265–270
122 Muoio, D. M. and Newgard, C. B. (2006) Obesityrelated derangements in metabolic regulation.
Annu. Rev. Biochem. 75, 367–401
C
2007 The Biochemical Society
123 He, W., Lam, T. K., Obici, S. and Rossetti, L. (2006)
Molecular disruption of hypothalamic nutrient sensing
induces obesity. Nat. Neurosci. 9, 227–233
124 Lam, T. K., Pocai, A., Gutierrez-Juarez, R. et al. (2005)
Hypothalamic sensing of circulating fatty acids is
required for glucose homeostasis. Nat. Med. 11, 320–327
125 Niswender, K. D., Morrison, C. D., Clegg, D. J. et al.
(2003) Insulin activation of phosphatidylinositol 3-kinase
in the hypothalamic arcuate nucleus: a key mediator of
insulin-induced anorexia. Diabetes 52, 227–231
126 Obici, S., Feng, Z., Karkanias, G., Baskin, D. G. and
Rossetti, L. (2002) Decreasing hypothalamic insulin
receptors causes hyperphagia and insulin resistance in
rats. Nat. Neurosci. 5, 566–572
127 Air, E. L., Strowski, M. Z., Benoit, S. C. et al. (2002) Small
molecule insulin mimetics reduce food intake and body
weight and prevent development of obesity. Nat. Med. 8,
179–183
128 Bergman, R. N., Finegood, D. T. and Kahn, S. E. (2002)
The evolution of β-cell dysfunction and insulin resistance
in type 2 diabetes. Eur. J. Clin. Invest 32 (Suppl. 3),
35–45
129 Campfield, L. A., Smith, F. J., Guisez, Y., Devos, R. and
Burn, P. (1995) Recombinant mouse OB protein: evidence
for a peripheral signal linking adiposity and central neural
networks. Science 269, 546–549
130 Harris, R. B., Zhou, J., Redmann, Jr, S. M. et al. (1998) A
leptin dose-response study in obese (ob/ob) and lean (+/?)
mice. Endocrinology 139, 8–19
131 Rentsch, J., Levens, N. and Chiesi, M. (1995)
Recombinant ob-gene product reduces food intake in
fasted mice. Biochem. Biophys. Res. Commun. 214,
131–136
132 Tartaglia, L. A., Dembski, M., Weng, X. et al. (1995)
Identification and expression cloning of a leptin receptor,
OB-R. Cell 83, 1263–1271
133 Ahima, R. S., Prabakaran, D., Mantzoros, C. et al. (1996)
Role of leptin in the neuroendocrine response to fasting.
Nature 382, 250–252
134 Friedman, J. M. (2000) Obesity in the new millennium.
Nature 404, 632–634
135 Fei, H., Okano, H. J., Li, C. et al. (1997) Anatomic
localization of alternatively spliced leptin receptors
(Ob-R) in mouse brain and other tissues. Proc. Natl.
Acad. Sci. U.S.A. 94, 7001–7005
136 Bryson, J. M., Phuyal, J. L., Proctor, D. R., Blair, S. C.,
Caterson, I. D. and Cooney, G. J. (1999) Plasma insulin
rise precedes rise in ob mRNA expression and plasma
leptin in gold thioglucose-obese mice. Am. J. Physiol.
276, E358–E364
137 Cummings, D. E., Purnell, J. Q., Frayo, R. S.,
Schmidova, K., Wisse, B. E. and Weigle, D. S. (2001) A
preprandial rise in plasma ghrelin levels suggests a role in
meal initiation in humans. Diabetes 50, 1714–1719
138 McCowen, K. C., Maykel, J. A., Bistrian, B. R. and Ling,
P. R. (2002) Circulating ghrelin concentrations are
lowered by intravenous glucose or hyperinsulinemic
euglycemic conditions in rodents. J. Endocrinol. 175,
R7–R11
139 Saad, M. F., Bernaba, B., Hwu, C. M. et al. (2002) Insulin
regulates plasma ghrelin concentration. J. Clin.
Endocrinol. Metab. 87, 3997–4000
140 Shiiya, T., Nakazato, M., Mizuta, M. et al. (2002) Plasma
ghrelin levels in lean and obese humans and the effect of
glucose on ghrelin secretion. J. Clin. Endocrinol. Metab.
87, 240–244
141 Ishii, S., Kamegai, J., Tamura, H., Shimizu, T.,
Sugihara, H. and Oikawa, S. (2002) Role of ghrelin in
streptozotocin-induced diabetic hyperphagia.
Endocrinology 143, 4934–4937
142 English, P. J., Ghatei, M. A., Malik, I. A., Bloom, S. R. and
Wilding, J. P. (2002) Food fails to suppress ghrelin levels
in obese humans. J. Clin. Endocrinol. Metab. 87, 2984
143 Cummings, D. E., Clement, K., Purnell, J. Q. et al. (2002)
Elevated plasma ghrelin levels in Prader Willi syndrome.
Nat. Med. 8, 643–644
144 Wynne, K., Stanley, S., McGowan, B. and Bloom, S.
(2005) Appetite control. J. Endocrinol. 184, 291–318
Diet, obesity and diabetes
145 Wren, A. M., Seal, L. J., Cohen, M. A. et al. (2001)
Ghrelin enhances appetite and increases food intake in
humans. J. Clin. Endocrinol. Metab. 86, 5992
146 Sun, Y., Asnicar, M., Saha, P. K., Chan, L. and Smith,
R. G. (2006) Ablation of ghrelin improves the diabetic but
not obese phenotype of ob/ob mice. Cell Metab. 3,
379–386
147 Kahn, B. B., Alquier, T., Carling, D. and Hardie, D. G.
(2005) AMP-activated protein kinase: ancient energy
gauge provides clues to modern understanding of
metabolism. Cell Metab. 1, 15–25
148 Carling, D. (2004) The AMP-activated protein kinase
cascade: a unifying system for energy control.
Trends Biochem. Sci. 29, 18–24
149 Minokoshi, Y., Alquier, T., Furukawa, N. et al. (2004)
AMP-kinase regulates food intake by responding to
hormonal and nutrient signals in the hypothalamus.
Nature 428, 569–574
150 Pocai, A., Muse, E. D. and Rossetti, L. (2006) Did a
muscle fuel gauge conquer the brain? Nat. Med. 12,
50–51
151 Niswender, K. D., Baskin, D. G. and Schwartz, M. W.
(2004) Insulin and its evolving partnership with leptin in
the hypothalamic control of energy homeostasis.
Trends Endocrinol. Metab. 15, 362–369
152 Woods, A., Dickerson, K., Heath, R. et al. (2005)
Ca2+/calmodulin-dependent protein kinase kinase-β acts
upstream of AMP-activated protein kinase in mammalian
cells. Cell Metab. 2, 21–33
153 Ning, K., Miller, L. C., Laidlaw, H. A. et al. (2006) A
novel leptin signalling pathway via PTEN inhibition in
hypothalamic cell lines and pancreatic beta-cells.
EMBO J. 25, 2377–2387
154 Lin, S., Storlien, L. H. and Huang, X. F. (2000) Leptin
receptor, NPY, POMC mRNA expression in the
diet-induced obese mouse brain. Brain Res. 875,
89–95
155 Ziotopoulou, M., Mantzoros, C. S., Hileman, S. M. and
Flier, J. S. (2000) Differential expression of hypothalamic
neuropeptides in the early phase of diet-induced obesity
in mice. Am. J. Physiol. Endocrinol. Metab. 279,
E838–E845
156 Accili, D. and Arden, K. C. (2004) FoxOs at the
crossroads of cellular metabolism, differentiation, and
transformation. Cell 117, 421–426
157 Kitamura, T., Feng, Y., Ido, K. Y. et al. (2006) Forkhead
protein FoxO1 mediates Agrp-dependent effects of leptin
on food intake. Nat. Med. 12, 534–540
158 Weigle, D. S. (1994) Appetite and the regulation of body
composition. FASEB J. 8, 302–310
159 Burgeson, C. R., Wechsler, H., Brener, N. D., Young, J. C.
and Spain, C. G. (2001) Physical education and activity:
results from the School Health Policies and Programs
Study 2000. J. Sch. Health 71, 279–293
160 Joosen, A. M., Gielen, M., Vlietinck, R. and Westerterp,
K. R. (2005) Genetic analysis of physical activity in twins.
Am. J. Clin. Nutr. 82, 1253–1259
161 Jeon, J. Y., Bradley, R. L., Kokkotou, E. G. et al. (2006)
MCH−/− mice are resistant to aging-associated increases
in body weight and insulin resistance. Diabetes 55,
428–434
162 Chen, G., Koyama, K., Yuan, X. et al. (1996)
Disappearance of body fat in normal rats induced by
adenovirus-mediated leptin gene therapy. Proc. Natl.
Acad. Sci. U.S.A. 93, 14795–14799
163 Levin, N., Nelson, C., Gurney, A., Vandlen, R. and
de Sauvage, F. (1996) Decreased food intake does not
completely account for adiposity reduction after ob
protein infusion. Proc. Natl. Acad. Sci. U.S.A. 93,
1726–1730
164 Pelleymounter, M. A., Cullen, M. J., Baker, M. B. et al.
(1995) Effects of the obese gene product on body weight
regulation in ob/ob mice. Science 269, 540–543
165 Hwa, J. J., Fawzi, A. B., Graziano, M. P. et al. (1997)
Leptin increases energy expenditure and selectively
promotes fat metabolism in ob/ob mice. Am. J. Physiol.
272, R1204–R1209
166 Halaas, J. L., Boozer, C., Blair-West, J., Fidahusein, N.,
Denton, D. A. and Friedman, J. M. (1997) Physiological
response to long-term peripheral and central leptin
infusion in lean and obese mice. Proc. Natl.
Acad. Sci. U.S.A. 94, 8878–8883
167 Halaas, J. L., Gajiwala, K. S., Maffei, M. et al. (1995)
Weight-reducing effects of the plasma protein encoded by
the obese gene. Science 269, 543–546
168 Yamada, T., Katagiri, H., Ishigaki, Y. et al. (2006) Signals
from intra-abdominal fat modulate insulin and leptin
sensitivity through different mechanisms: neuronal
involvement in food-intake regulation. Cell Metab. 3,
223–229
169 Qi, Y., Takahashi, N., Hileman, S. M. et al. (2004)
Adiponectin acts in the brain to decrease body weight.
Nat. Med. 10, 524–529
170 Combs, T. P., Berg, A. H., Obici, S., Scherer, P. E. and
Rossetti, L. (2001) Endogenous glucose production is
inhibited by the adipose-derived protein Acrp30.
J. Clin. Invest. 108, 1875–1881
171 Yamauchi, T., Kamon, J., Minokoshi, Y. et al. (2002)
Adiponectin stimulates glucose utilization and fatty-acid
oxidation by activating AMP-activated protein kinase.
Nat. Med. 8, 1288–1295
172 Ronti, T., Lupattelli, G. and Mannarino, E. (2006) The
endocrine function of adipose tissue: an update.
Clin. Endocrinol. 64, 355–365
173 Elliott, S. S., Keim, N. L., Stern, J. S., Teff, K. and Havel,
P. J. (2002) Fructose, weight gain, and the insulin
resistance syndrome. Am. J. Clin. Nutr. 76, 911–922
174 Daly, M. (2003) Sugars, insulin sensitivity, and the
postprandial state. Am. J. Clin. Nutr. 78, 865S-872S
175 Smith, U. (1994) Carbohydrates, fat, and insulin action.
Am. J. Clin. Nutr. 59, 686S–689S
176 Ruderman, N. B., Saha, A. K. and Kraegen, E. W. (2003)
Minireview: malonyl CoA, AMP-activated protein
kinase, and adiposity. Endocrinology 144, 5166–5171
177 Saha, A. K. and Ruderman, N. B. (2003) Malonyl-CoA
and AMP-activated protein kinase: an expanding
partnership. Mol. Cell. Biochem. 253, 65–70
178 Guillet-Deniau, I., Pichard, A. L., Kone, A. et al. (2004)
Glucose induces de novo lipogenesis in rat muscle satellite
cells through a sterol-regulatory-element-bindingprotein-1c-dependent pathway. J. Cell Sci. 117,
1937–1944
179 Aas, V., Kase, E. T., Solberg, R., Jensen, J. and Rustan,
A. C. (2004) Chronic hyperglycaemia promotes
lipogenesis and triacylglycerol accumulation in human
skeletal muscle cells. Diabetologia 47, 1452–1461
180 Abu-Elheiga, L., Matzuk, M. M., Abo-Hashema, K. A.
and Wakil, S. J. (2001) Continuous fatty acid
oxidation and reduced fat storage in mice lacking acetylCoA carboxylase 2. Science 291, 2613–2616
181 Bastie, C. C., Hajri, T., Drover, V. A., Grimaldi, P. A. and
Abumrad, N. A. (2004) CD36 in myocytes channels fatty
acids to a lipase-accessible triglyceride pool that is related
to cell lipid and insulin responsiveness. Diabetes 53,
2209–2216
182 Blaak, E. E. (2004) Basic disturbances in skeletal muscle
fatty acid metabolism in obesity and type 2 diabetes
mellitus. Proc. Nutr. Soc. 63, 323–330
183 Bezaire, V., Bruce, C. R., Heigenhauser, G. J. et al. (2006)
Identification of fatty acid translocase on human skeletal
muscle mitochondrial membranes: essential role in fatty
acid oxidation. Am. J. Physiol. Endocrinol. Metab. 290,
E509–E515
184 Hulver, M. W., Berggren, J. R., Carper, M. J. et al. (2005)
Elevated stearoyl-CoA desaturase-1 expression in skeletal
muscle contributes to abnormal fatty acid partitioning in
obese humans. Cell Metab. 2, 251–261
185 Curry, D. L. (1989) Effects of mannose and fructose on
the synthesis and secretion of insulin. Pancreas 4, 2–9
186 Havel, P. J. (2005) Dietary fructose: implications for
dysregulation of energy homeostasis and lipid/
carbohydrate metabolism. Nutr. Rev. 63, 133–157
187 Bizeau, M. E. and Pagliassotti, M. J. (2005) Hepatic
adaptations to sucrose and fructose. Metab., Clin. Exp.
54, 1189–1201
C
2007 The Biochemical Society
109
110
C. G. Walker and others
188 Taghibiglou, C., Carpentier, A., Van Iderstine, S. C. et al.
(2000) Mechanisms of hepatic very low density
lipoprotein overproduction in insulin resistance. Evidence
for enhanced lipoprotein assembly, reduced intracellular
ApoB degradation, and increased microsomal triglyceride
transfer protein in a fructose-fed hamster model.
J. Biol. Chem. 275, 8416–8425
189 Hirano, T., Mamo, J. C., Poapst, M. E., Kuksis, A. and
Steiner, G. (1989) Impaired very low-density
lipoprotein-triglyceride catabolism in acute and chronic
fructose-fed rats. Am. J. Physiol. 256, E559–E565
190 Bezerra, R. M., Ueno, M., Silva, M. S., Tavares, D. Q.,
Carvalho, C. R. and Saad, M. J. (2000) A high fructose
diet affects the early steps of insulin action in muscle and
liver of rats. J. Nutr. 130, 1531–1535
191 Osei, K., Falko, J., Bossetti, B. M. and Holland, G. C.
(1987) Metabolic effects of fructose as a natural sweetener
in the physiologic meals of ambulatory obese patients
with type II diabetes. Am. J. Med. 83, 249–255
192 Koivisto, V. A. and Yki-Jarvinen, H. (1993) Fructose and
insulin sensitivity in patients with type 2 diabetes.
J. Intern. Med. 233, 145–153
193 Shiota, M., Galassetti, P., Monohan, M., Neal, D. W. and
Cherrington, A. D. (1998) Small amounts of fructose
markedly augment net hepatic glucose uptake in the
conscious dog. Diabetes 47, 867–873
194 Teff, K. L., Elliott, S. S., Tschop, M. et al. (2004) Dietary
fructose reduces circulating insulin and leptin, attenuates
postprandial suppression of ghrelin, and increases
triglycerides in women. J. Clin. Endocrinol. Metab. 89,
2963–2972
195 Miyazaki, M., Dobrzyn, A., Man, W. C. et al. (2004)
Stearoyl-CoA desaturase 1 gene expression is necessary
for fructose-mediated induction of lipogenic gene
expression by sterol regulatory element-binding
protein-1c-dependent and -independent mechanisms.
J. Biol. Chem. 279, 25164–25171
196 Hajri, T. and Abumrad, N. A. (2002) Fatty acid transport
across membranes: relevance to nutrition and metabolic
pathology. Annu. Rev. Nutr. 22, 383–415
197 Coburn, C. T., Knapp, Jr, F. F., Febbraio, M., Beets, A. L.,
Silverstein, R. L. and Abumrad, N. A. (2000) Defective
uptake and utilization of long chain fatty acids in muscle
and adipose tissues of CD36 knockout mice.
J. Biol. Chem. 275, 32523–32529
198 Hajri, T., Han, X. X., Bonen, A. and Abumrad, N. A.
(2002) Defective fatty acid uptake modulates insulin
responsiveness and metabolic responses to diet in
CD36-null mice. J. Clin. Invest 109, 1381–1389
199 Kim, J. K., Gimeno, R. E., Higashimori, T. et al. (2004)
Inactivation of fatty acid transport protein 1 prevents
fat-induced insulin resistance in skeletal muscle.
J. Clin. Invest 113, 756–763
200 Wu, Q., Ortegon, A. M., Tsang, B., Doege, H., Feingold,
K. R. and Stahl, A. (2006) FATP1 is an insulin-sensitive
fatty acid transporter involved in diet-induced obesity.
Mol. Cell. Biol. 26, 3455–3467
201 Smith, A. J., Sanders, M. A., Thompson, B. R.,
Londos, C., Kraemer, F. B. and Bernlohr, D. A. (2004)
Physical association between the adipocyte fatty
acid-binding protein and hormone-sensitive lipase:
a fluorescence resonance energy transfer analysis.
J. Biol. Chem. 279, 52399–52405
202 Baar, R. A., Dingfelder, C. S., Smith, L. A. et al. (2005)
Investigation of in vivo fatty acid metabolism in AFABP/
aP2−/− mice. Am. J. Physiol. Endocrinol. Metab. 288,
E187–E193
203 Martinez-Botas, J., Anderson, J. B., Tessier, D. et al.
(2000) Absence of perilipin results in leanness and reverses
obesity in Leprdb/db mice. Nat. Genet. 26, 474–479
204 Hu, F. B., van Dam, R. M. and Liu, S. (2001) Diet and risk
of Type II diabetes: the role of types of fat and
carbohydrate. Diabetologia 44, 805–817
205 Storlien, L. H., Huang, X. F., Lin, S., Xin, X., Wang,
H. Q. and Else, P. L. (2001) Dietary fat subtypes and
obesity. World Rev. Nutr. Diet. 88, 148–154
C
2007 The Biochemical Society
206 Storlien, L. H., Jenkins, A. B., Chisholm, D. J., Pascoe,
W. S., Khouri, S. and Kraegen, E. W. (1991) Influence of
dietary fat composition on development of insulin
resistance in rats. Relationship to muscle triglyceride and
omega-3 fatty acids in muscle phospholipid. Diabetes 40,
280–289
207 Taouis, M., Dagou, C., Ster, C., Durand, G., Pinault, M.
and Delarue, J. (2002) N-3 polyunsaturated fatty acids
prevent the defect of insulin receptor signaling in muscle.
Am. J. Physiol. Endocrinol. Metab. 282, E664–E671
208 Corporeau, C., Foll, C. L., Taouis, M., Gouygou, J. P.,
Berge, J. P. and Delarue, J. (2006) Adipose tissue
compensates for defect of phosphatidylinositol 3 -kinase
induced in liver and muscle by dietary fish oil in fed rats.
Am. J. Physiol. Endocrinol. Metab. 290, E78–E86
209 Lombardo, Y. B. and Chicco, A. G. (2006) Effects of
dietary polyunsaturated n-3 fatty acids on dyslipidemia
and insulin resistance in rodents and humans. A review.
J. Nutr. Biochem. 17, 1–13
210 Ailhaud, G., Massiera, F., Weill, P., Legrand, P.,
Alessandri, J. M. and Guesnet, P. (2006) Temporal changes
in dietary fats: role of n-6 polyunsaturated fatty acids in
excessive adipose tissue development and relationship to
obesity. Prog. Lipid Res. 45, 203–236
211 Holness, M. J., Greenwood, G. K., Smith, N. D. and
Sugden, M. C. (2003) Diabetogenic impact of long-chain
omega-3 fatty acids on pancreatic β-cell function and the
regulation of endogenous glucose production.
Endocrinology 144, 3958–3968
212 Lin, Q., Ruuska, S. E., Shaw, N. S., Dong, D. and Noy, N.
(1999) Ligand selectivity of the peroxisome proliferatoractivated receptor α. Biochemistry 38, 185–190
213 Patsouris, D., Reddy, J. K., Muller, M. and Kersten, S.
(2006) Peroxisome proliferator-activated receptor α
mediates the effects of high-fat diet on hepatic gene
expression. Endocrinology 147, 1508–1516
214 de Fourmestraux, V., Neubauer, H., Poussin, C. et al.
(2004) Transcript profiling suggests that differential
metabolic adaptation of mice to a high fat diet is
associated with changes in liver to muscle lipid fluxes.
J. Biol. Chem. 279, 50743–50753
215 He, J. and Kelley, D. E. (2004) Muscle glycogen content
in type 2 diabetes mellitus. Am. J. Physiol.
Endocrinol. Metab. 287, E1002–E1007
216 Pan, D. A., Lillioja, S., Kriketos, A. D. et al. (1997)
Skeletal muscle triglyceride levels are inversely related to
insulin action. Diabetes 46, 983–988
217 Krssak, M., Falk, P. K., Dresner, A. et al. (1999)
Intramyocellular lipid concentrations are correlated with
insulin sensitivity in humans: a 1H NMR spectroscopy
study. Diabetologia 42, 113–116
218 Febbraio, M., Abumrad, N. A., Hajjar, D. P. et al. (1999)
A null mutation in murine CD36 reveals an important
role in fatty acid and lipoprotein metabolism.
J. Biol. Chem. 274, 19055–19062
219 Ibrahimi, A., Bonen, A., Blinn, W. D. et al. (1999)
Muscle-specific overexpression of FAT/CD36 enhances
fatty acid oxidation by contracting muscle, reduces
plasma triglycerides and fatty acids, and increases plasma
glucose and insulin. J. Biol. Chem. 274, 26761–26766
220 Febbraio, M., Guy, E., Coburn, C. et al. (2002) The impact
of overexpression and deficiency of fatty acid translocase
(FAT)/CD36. Mol. Cell. Biochem. 239, 193–197
221 Chavez, J. A. and Summers, S. A. (2003) Characterizing
the effects of saturated fatty acids on insulin signaling and
ceramide and diacylglycerol accumulation in 3T3-L1
adipocytes and C2C12 myotubes. Arch. Biochem.
Biophys. 419, 101–109
222 Chavez, J. A., Holland, W. L., Bar, J., Sandhoff, K. and
Summers, S. A. (2005) Acid ceramidase overexpression
prevents the inhibitory effects of saturated fatty acids on
insulin signaling. J. Biol. Chem. 280, 20148–20153
223 Yu, C., Chen, Y., Cline, G. W. et al. (2002) Mechanism by
which fatty acids inhibit insulin activation of insulin
receptor substrate-1 (IRS-1)-associated
phosphatidylinositol 3-kinase activity in muscle.
J. Biol. Chem. 277, 50230–50236
Diet, obesity and diabetes
224 Arkan, M. C., Hevener, A. L., Greten, F. R. et al. (2005)
IKK-β links inflammation to obesity-induced insulin
resistance. Nat. Med. 11, 191–198
225 Nagai, Y., Nishio, Y., Nakamura, T., Maegawa, H.,
Kikkawa, R. and Kashiwagi, A. (2002) Amelioration of
high fructose-induced metabolic derangements by
activation of PPARα. Am. J. Physiol. Endocrinol. Metab.
282, E1180–E1190
226 Furuhashi, M., Ura, N., Murakami, H. et al. (2002)
Fenofibrate improves insulin sensitivity in connection
with intramuscular lipid content, muscle fatty
acid-binding protein, and β-oxidation in skeletal muscle.
J. Endocrinol. 174, 321–329
227 Ye, J. M., Iglesias, M. A., Watson, D. G. et al. (2003)
PPARα/γ ragaglitazar eliminates fatty liver and enhances
insulin action in fat-fed rats in the absence of
hepatomegaly. Am. J. Physiol. Endocrinol. Metab. 284,
E531–E540
228 Holness, M. J., Smith, N. D., Greenwood, G. K. and
Sugden, M. C. (2003) Acute (24 h) activation of
peroxisome proliferator-activated receptor-α (PPARα)
reverses high-fat feeding-induced insulin hypersecretion
in vivo and in perifused pancreatic islets. J. Endocrinol.
177, 197–205
229 Suchankova, G., Tekle, M., Saha, A. K., Ruderman, N. B.,
Clarke, S. D. and Gettys, T. W. (2005) Dietary
polyunsaturated fatty acids enhance hepatic AMPactivated protein kinase activity in rats.
Biochem. Biophys. Res. Commun. 326, 851–858
230 Carling, D. (2005) AMP-activated protein kinase:
balancing the scales. Biochimie 87, 87–91
231 Viollet, B., Andreelli, F., Jorgensen, S. B. et al. (2003) The
AMP-activated protein kinase α2 catalytic subunit
controls whole-body insulin sensitivity. J. Clin. Invest.
111, 91–98
232 Viollet, B., Andreelli, F., Jorgensen, S. B. et al. (2003)
Physiological role of AMP-activated protein kinase
(AMPK): insights from knockout mouse models.
Biochem. Soc. Trans. 31, 216–219
233 Barnes, B. R. and Zierath, J. R. (2005) Role of AMP–
activated protein kinase in the control of glucose
homeostasis. Curr. Mol. Med. 5, 341–348
234 Barnes, B. R., Marklund, S., Steiler, T. L. et al. (2004)
The 5 -AMP-activated protein kinase γ 3 isoform
has a key role in carbohydrate and lipid metabolism in
glycolytic skeletal muscle. J. Biol. Chem. 279,
38441–38447
235 Pocai, A., Lam, T. K., Obici, S. et al. (2006) Restoration of
hypothalamic lipid sensing normalizes energy and glucose
homeostasis in overfed rats. J. Clin. Invest. 116,
1081–1091
236 Wang, J., Obici, S., Morgan, K., Barzilai, N., Feng, Z. and
Rossetti, L. (2001) Overfeeding rapidly induces leptin
and insulin resistance. Diabetes 50, 2786–2791
237 Morgan, K., Obici, S. and Rossetti, L. (2004)
Hypothalamic responses to long-chain fatty acids are
nutritionally regulated. J. Biol. Chem. 279,
31139–31148
Received 16 June 2006/4 August 2006; accepted 29 August 2006
Published on the Internet 11 December 2006, doi:10.1042/CS20060150
C
2007 The Biochemical Society
111