c h a p t e r

36
Role of the Adipocyte in
Metabolism and Endocrine
Function
Eric Ravussin and Steven R. Smith

CHAPTER OUTLINE
OBESITY, INSULIN RESISTANCE, INFLAMMATION,
ER STRESS, AND TYPE 2 DIABETES MELLITUS, 628
Link Between Obesity and Insulin Resistance, 628
Links Between Obesity, Inflammation, and ER
Stress, 631
Link Between Too Little Fat and Insulin
Resistance, 632
Brown Adipose Tissue in Humans, 637
Integrative Biology of the Adipose Tissue, 639
Endocrine Signals, 639
Neural Signals to the Adipose Tissue, 640
Regulation of Lipolysis, 640
Adipocyte as an Endocrine Organ, 641
The Adipocyte as a Target for the Treatment of
Obesity and Type 2 Diabetes, 646

KEY POINTS
• A dipose tissue development and dysfunction plays a central role in several diseases
including type 2 diabetes, cardiovascular disease, and metabolic health.
• Once considered to be simply a passive fat storage organ, adipose tissue is a complex
endocrine organ and plays a central role in energy homeostasis and metabolic health.
• When the energy input exceeds the capacity for storage, adipose tissue becomes
dysfunctional and a liability for metabolic health.
• Adipose tissue dysfunction includes changes in hormone secretion, inflammation, and
alterations in lipid and glucose metabolism.
  

In an evolutionary sense, the adipose tissue represents the
most efficient way to store energy in periods of feast to
allow survival during periods of famine. There are two
main reasons for this efficiency. First, on a weight basis,
triacylglycerol, commonly called triglycerides, yields
more than two times the amount of energy as glycogen
or proteins. Second, triglycerides are stored without asso-
ciated water whereas glycogen, which is hydrophilic,
binds as much as twice its weight to water. Similarly,
proteins, the building blocks of cells, are associated with
large amounts of water. As a result, the energy that can
be recovered from triglyceride stores by unit of weight is
more than four times larger than that from glycogen and/
or protein stores. An average 75-kg man can store only
approximately 500 g of carbohydrate in liver and muscle,
representing less than 1 day of energy stores. By contrast,
even in lean individuals, fat stores in the adipose tissue
alone can amount to approximately 10 kg, which is suf-
ficient to maintain bodily functions for weeks of survival
during total food deprivation. In obesity, fat stores can
be multiplied by as much as 10 to 20 times and provide
energy for months of starvation. The energy content of
and the deficit required to lose 1 pound of body weight
was originally determined to be 3500 kcal; however, more
recent calculations show that this is generally true but
varies depending on the actual initial body weight, sex,
and body composition.1 The energy from triglycerides
is stored in some 25 to 50 billion fat cells representing
the adipose tissue, mostly beneath the skin (subcutane-
ous adipose tissue) and in the abdomen. Until only 20
years ago, the adipose tissue was primarily considered as
an energy storage compartment providing energy fuel to
627
628 PART 5 DIABETES MELLITUS

the entire body in-between meals and during periods of
energy deficit.
With the discovery of leptin in 19942 and the many
other secreted proteins discovered since,3 adipose tissue
is now not only considered as an energy reservoir but
has reached the status of a true endocrine organ. Over
the past decade, effort has been concentrated on a better
understanding of the regulation of adipose tissue devel-
opment and apoptosis/turnover throughout the life span
and its consequence on health and diseases. In this chap-
ter, we will review the role of the adipose as an energy
storage compartment, but more importantly we will sum-
marize the current knowledge of what is now considered
as a finely tuned endocrine organ, which can influence
many facets of the conditions often referred as metabolic
syndrome. We will first describe the links between too
much fat (obesity), inflammation, endoplasmic reticu-
lum (ER) stress, and insulin resistance and, alternatively,
provide arguments why too little fat is equally and para-
doxically associated with insulin resistance. Next, we
will review the pioneering work that led to the concept
of hypertrophic and hyperplastic obesity and the criti-
cal periods during which the adipose tissue is thought to
develop. The current understanding of the regulation of
adipogenesis is then reviewed, followed by a description
of the afferent endocrine and neural signals to the adipose
tissue. We will also provide new information regarding
the potential importance of brown adipose tissue (BAT)
in humans, a concept that was discarded over the past 2
decades because of the belief that such tissue was lack-
ing in adult humans. In the next section, we will discuss
the lipostatic theory, which led to the discovery of leptin
and many other hormones involved in health and disease.
Beside leptin, we will provide additional details on adipo-
nectin, resistin, TNF-α, apelin, and adipose. We conclude
by proposing the adipocyte as a potential target for the
treatment of obesity, dyslipidemia, and type 2 diabetes,
with emphasis on inducing BAT.
OBESITY, INSULIN RESISTANCE, INFLAMMATION, ER
STRESS, AND TYPE 2 DIABETES MELLITUS
Link Between Obesity and Insulin Resistance
Numerous cross-sectional studies have shown an associa-
tion between obesity and type 2 diabetes (Figs. 36-1 and
36-2). Data from the third National Health Examination
Survey (NHANES III) provides unequivocal evidence that
the prevalence of diabetes is almost three times higher
in overweight individuals than in nonoverweight indi-
viduals.4 Many prospective studies have confirmed this
association. As an example, the likelihood of developing

CHRONIC ENERGY EXCESS

Obesity

Failure of Fetal Failure of

vascularization programming differentiation

↓ Adiponectin Adipocyte ER stress Inflammatory

↑ Leptin Hypertrophy cytokines

Decreased capillary
density and/or Chemokine
vasoconstriction secretion

Disordered lipid Macrophage

Hypoxia recruitment
metabolism Mitochondrial Chemokine
and activation
dysfunction secretion

Apoptosis

Figure 36-1 Obesity and adipocyte hypertrophy. Adipocyte hypertrophy is a key feature of the insulin-resistant state. The flux of free fatty acids
out of adipose tissue is disordered in obesity, especially when adipocyte hypertrophy is present. In addition, hypoxia, inflammation, and endoplasmic
reticulum (ER) stress have been implicated as important mechanistic links between obesity and insulin resistance. This figure attempts to reconcile the
available data on how obesity might lead to insulin resistance. In many instances, the directionality of the connections between mechanistic factors is
unclear. For example, it is clear that ER stress can lead to the secretion of inflammatory cytokines, but it is not entirely clear if inflammation and mac-
rophages might lead to ER stress. Similarly, reduced capillary density (rarefaction) leads to hypoxia, and hypoxia leads to the secretion of chemokines
and inflammatory cytokines and probably disordered adipokine secretion. Hypertrophic adipocytes secrete the inflammatory peptide SAA, which
may serve to amplify inflammation and chemotaxis of macrophages. At this time, it is difficult to disentangle the web of deleterious connections. It
appears that once the cascade is initiated, there are multiple interlocking pathways that may sustain the dysfunctional adipose tissue. (From Yang RZ,
Lee MJ, Hu H, et al. Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.
PLoS Med 3[6]:e287, 2006; and Jernas M, Palming J, Sjoholm K, et al. Separation of human adipocytes by size: hypertrophic fat cells display distinct
gene expression. FASEB J 20[9]:1540-1542, 2006.)
 36 ROLE OF THE ADIPOCYTE IN METABOLISM AND ENDOCRINE FUNCTION 629

A B

C D

n
F
E
Figure 36-2 Angiogenesis and innervations in adipose tissue. Adipose tissue has the capacity to grow new blood vessels. A, Adipose tissue fragments
show outgrowth of new capillaries after 10 days of culture ex-vivo. B, In human adipose tissue, capillaries form a rich meshwork around adipocytes.
Adipocytes are stained green (BODIPY), and capillaries are stained red (Lectin UEA). In obesity, capillary density is decreased in subcutaneous adi-
pose tissue. Obese adipose tissue (C) and lean adipose tissue (D) have different capillary density. Adipocyte plasmalemma is stained green with Lectin-
GS, and capillaries are stained red with Lectin UEA. Human adipose tissue is innervated with sympathetic nervous system (SNS) nerve terminals that
are important for the activation of lipolysis. E, Fluorescent immunohistochemistry of nerve fibers (neural-specific antibody) in white adipose tissue.
F, SNS-specific staining with tyrosine hydroxylase. (A, Photomicrograph courtesy of Dr. Frank Greenway, Pennington Biomedical Research Center;
methods as in Greenway FL, Liu Z, Yu Y, et al. An assay to measure angiogenesis in human fat tissue. Obes Surg 17[4]:510-515, 2007. B, Photomi-
crograph courtesy of Drs. Magdalena Pasarica, David Burk, and Steven Smith, Pennington Biomedical Research Center. C, Methods are presented
in Trayhurn P, Wang B, Wood IS. Hypoxia and the endocrine and signalling role of white adipose tissue. Arch Physiol Biochem 114[4]:267-276,
2008. E and F, Reprinted with permission from Giordano A, Song CK, Bowers RR, et al. White adipose tissue lacks significant vagal innervation and
immunohistochemical evidence of parasympathetic innervation. Am J Physiol Regul Integr Comp Physiol 291[5]:R1243-R1255, 2006.)
630 PART 5 DIABETES MELLITUS
diabetes increases steeply with increasing body weight
and fatness in Pima Indians.5 The reason for the asso-
ciation between obesity and diabetes is attributed mostly
to the increase in insulin resistance so common in obese
people.6 Insulin resistance is a clear predisposing factor
for the development of type 2 diabetes in individuals at
risk for the disease.7-9
Obesity is usually characterized by increased circulat-
ing plasma free-fatty acid (FFA) concentration. Studies in
animals and humans support a causal effect of elevated
FFA (produced by lipolysis of triglycerides from adipose
tissue) on impaired insulin-mediated glucose metabo-
lism.10-13 Such studies reinforce the original hypothesis
proposed by Randle and colleagues in 196314,15 and later
by McGarry16 that altered fatty acid metabolism was the
key contributing factor to insulin resistance in obese and
diabetic patients. Randle and colleagues demonstrated
that FFAs compete with glucose for substrate oxidation
in isolated preparations of heart and diaphragm muscle
from rats. More specifically, they proposed that increased
fatty acid availability in obesity causes an increase in the
intramitochondrial acetyl-CoA/CoA and NADH/NAD+
ratios, leading to inactivation of the enzyme pyruvate
dehydrogenase. This, in turn, causes an intracellular
increase in citrate concentration, leading to inhibition of
phosphofructokinase, the rate-limiting enzyme for glycol-
ysis. As a consequence, glucose-6-phosphate accumulates
in the cell and inhibits hexokinase II activity, leading to
an increase in intracellular glucose and a decrease in glu-
cose uptake, oxidation, and storage.
Randle’s glucose–fatty acid cycle has been challenged
by data from sophisticated clinical studies using stable
isotope turnover in conjunction with substrate leg bal-
ance methods or using 13C and 31P magnetic resonance
spectroscopy. These studies provide evidence that insulin
resistance in obese individuals may be related to a pri-
mary defect of fatty acid oxidation in skeletal muscle
rather than a competition between fat and carbohydrate
metabolism.
First, Wolfe and associates identified some of the flaws
in the notion that fatty acid availability controls substrate
oxidation in the fasting state.17 He provided evidence
that fatty acid oxidation is largely controlled at the site of
oxidation, which is in turn determined by the availability
of glucose. In this model, the primary physiologic role
of increased adipose lipolysis in fasting conditions is to
provide the necessary glycerol as a gluconeogenic precur-
sor,18 and the rate of fatty acid oxidation is then regu-
lated by the rate of intracellular metabolism of glucose.
Second, it is now well accepted that skeletal muscle pre-
dominantly relies on lipid oxidation during fasting and can
easily switch from lipid to increased glucose uptake and
oxidation in response to feeding and hyperinsulinemia.19
This switch from fat to carbohydrate oxidation in skeletal
muscle has been called metabolic flexibility. Importantly,
Kelley and Mandarino provided convincing evidence that
glucose oxidation after an overnight fast is increased in
the leg of subjects with type 2 diabetes, thereby decreasing
its reliance on fat oxidation.20 In opposition to Randle’s
glucose-fatty acid cycle, their series of studies suggest that
hyperglycemia itself causes an impairment of the normal
fasting reliance of skeletal muscle on fatty acids, there-
fore causing an accumulation of lipids into the muscle
tissue. This “reversed Randle cycle” theory highlights the
primary role of impaired lipid oxidation in skeletal mus-
cle rather than excessive lipolysis in the adipose tissue.
Growing evidence suggests that the primary cause of the
“metabolic inflexibility” in subjects susceptible to insulin
resistance is impaired fat oxidation in the fasting state
rather than a lack of increased carbohydrate oxidation
in response to feeding.21 In support of this concept, there
is now evidence pointing toward decreased mitochon-
drial oxidative capacity in insulin-resistant subjects with
diabetes22 or family history of diabetes23 and in insulin-
resistant older adults.24
To prove or disprove the “Randle cycle” hypothesis,
Shulman and co-workers went one step further. If the
Randle hypothesis was true, one would predict an accu-
mulation of glucose-6-phosphate in the skeletal muscle
of healthy subjects during glucose and insulin infusions
in the presence of high plasma FFA concentration.25
They directly tested this hypothesis using magnetic reso-
nance spectroscopy. As expected, high concentrations of
circulating FFA caused a reduction in insulin-mediated
glucose uptake with an approximately 50% decrease
in glucose storage and 50% decrease in glucose oxida-
tion.12 However, in contrast to what would be predicted
by the Randle’s hypothesis, there was no accumulation of
glucose-6-phosphate. Therefore, reduced glucose uptake
when FFAs are high is due to impaired glucose transport
or impaired intracellular signaling. This series of stud-
ies shows that intramuscular fatty acids or fatty acid
metabolites seem to interfere with the transport of glu-
cose into the skeletal muscle cells. Studies have provided
some potential mechanisms of the effect of FFA-induced
insulin resistance via an impact on insulin signaling at
the level of protein kinase C θ.26-29 More recently how-
ever, Koves and colleagues, using targeted metabolomics,
found that obesity-related insulin resistance in skeletal
muscle is characterized by excessive beta-oxidation,
impaired switching to carbohydrate during the fasted-
to-fed transition, and simultaneous depletion of organic
intermediates of the tricarboxylic acid cycle.30 There-
fore, an excessive rather than reduced beta-oxidation
may underlie the development of muscle insulin resis-
tance by accumulation of acyl-CoAs and their respective
acyl-carnitines.30
While many studies have provided evidence for an
association between insulin sensitivity and visceral fat
mass (reviewed in reference 31), other studies provide evi-
dence just as good for associations between the amount
of subcutaneous fat on the trunk and insulin resistance in
obese nondiabetic men32,33 and in men with type 2 dia-
betes.20,34,35 Similarly, insulin resistance in obese women
is best related to overall elevated fat mass than just vis-
ceral fat mass.36,37 Thus, subcutaneous fat, which does
not drain into the portal vein, causes insulin resistance
by a nonportal mechanism. The growing experimen-
tal evidence, which does not support the Randle/portal
hypothesis, therefore calls for a change in the scientific
paradigm to explain the insulin resistance so common in
obesity. The bulk of the literature now provides evidence
 36 ROLE OF THE ADIPOCYTE IN METABOLISM AND ENDOCRINE FUNCTION
that excessive total fat mass (rather than just visceral fat
mass) and impaired muscle fat oxidation are associated
with insulin resistance and increased risk for the develop-
ment of type 2 diabetes.
In addition to the key role of total fat mass to the
metabolic disturbances described earlier, fat distribution
may play an important role in several aspects of meta-
bolic function. For example, some of our own studies
have clearly shown that the gluteal adipose tissue may be
protective against insulin resistance rather than precipi-
tating it.38 In contrast, visceral omental adipose tissue
exhibits more inflammation than subcutaneous adipose
tissue and intramuscular adipose tissue39-42 (the “mar-
bled” adipose tissue in between the muscles) and both
are associated with a greater cardiovascular and diabe-
tes risks. The mechanisms underlying these regional dif-
ferences in adipose tissue function and disease risk are
only now being elucidated and will be discussed later in
the chapter.
Links Between Obesity, Inflammation, and ER Stress
Studies in mice and humans suggested that adipose tis-
sue contains not only adipocytes and supporting cells,
but also macrophages (see Figs. 36-1 and 36-2).43,44 The
macrophage is responsible for consuming extracellular
bacteria, cellular debris, and lipids, whereas the adi-
pocyte is responsible for internalizing and sequestering
excess lipids. The macrophages appear to be the major
site of TNF-α secretion and may also secrete other cyto-
kines such as IL-8,45,46 an atherogenic cytokine pro-
duced in adipose tissue. These studies also suggested
that the bone marrow was the major site of origin for
the adipose tissue macrophages, suggesting that obesity
and diabetes might “recruit” these cells through the pro-
duction of one or more chemokines.47 The significance
of the inflammatory cells is that they are likely to acti-
vate the NF-κb signaling cascade, like TNF-α. Iκκ-β, the
upstream activator of NF-κb signaling, plays a key role
in insulin signaling and is necessary for the full expres-
sion of the insulin-resistant phenotype in the obese ob/
ob mouse.48 Upstream αα activators of this pathway
include not only TNF-α, but also fatty acids 49 and
bacterial lipopolysaccharide. Fatty acids activate this
pathway via the Toll-receptor 4, which also responds
to lipopolysaccharide.49 In vivo studies in mice48 and
humans50-52 demonstrate that salicylates, inhibitors of
the Iκκ-β pathway,53 play an important therapeutic role
in insulin resistance and diabetes,54 in part through adi-
pocyte-mediated pathways.55,56 The antidiabetic peroxi-
some proliferator-activated receptor γ (PPAR-γ) ligands
(e.g., TZDs) also decrease the gene transcriptional
effects of the Iκκ-β pathway.57
Many more inflammatory cytokines such as monocyte
chemoattractant protein-1 (MCP-1) and plasminogen
activator protein (PAI) have been linked to adiposity. The
increase in inflammatory cytokines found in obesity ulti-
mately characterizes excess adipose tissue as a state of
low-grade systemic inflammation, which may link obesity
to its comorbidities.58 Obesity therefore occurs in asso-
ciation with an increase in inflammatory cytokines and
an infiltration of macrophages within the adipose tissue.
631
Two of the major unsolved questions regarding this
observation are: Why does inflammation occur in parallel
with obesity, and what is the consequence of this inflam-
mation? One of the growing hypotheses first proposed
by Trayhurn’s group59 and more recently reviewed60,61 is
that inflammation is likely the result of reduced oxygen-
ation (hypoxia; see Figs. 36-1, 36-2, and 36-3) in adipose
tissue, which may provide cellular mechanisms for mac-
rophage infiltration, reduction in adiponectin secretion,
increased leptin secretion, adipocyte death, endoplasmic
reticulum (ER) stress, fibrosis, and mitochondrial dys-
function62 in white adipose tissue (WAT) in obesity.63-65
Inhibition of adipogenesis and triglyceride synthesis by
hypoxia may be a mechanism to elevate plasma FFA
and reduce adiponectin concentrations, both leading to
insulin resistance in obesity.63,64 The biological basis for
adipose tissue hypoxia could be related to a reduction in
arterial blood flow as a result of adipocytes outgrowing
their blood supply (Fig. 36-3). A failure to maintain blood
flow or reduced capillary density (a lack of compensa-
tory angiogenesis or vasoconstriction) may be the basis of
the observed reduction in blood flow in human adipose
tissue.60 The hypothesis that increased adipocyte mass
Fat
Gain of fat mass
(proliferation, differentiation, lipid storage)
Decreased Adipose tissue
capillary density vasoconstriction
Decreased adipose Insulin
tissue blood flow resistance
Adipose tissue hypoxia Inflammation
Angiogenesis and/or
vasodilation
Adipose tissue remodeling
Figure 36-3 Hypoxia, inflammation, and insulin resistance. Rap-
id growth of adipose tissue leads to an expansion that may not be
­accompanied by a simultaneous maintenance of capillary density by in-
creased angiogenesis or vasodilation and therefore may cause a decrease
in blood flow to the tissue. Decreased blood flow per unit of adipose tis-
sue leads to tissue hypoxia, which, in turn, induces inflammation. When
inflammation becomes out of control with increased systemic and local
cytokine concentrations, insulin resistance occurs. Adipose hypoxia is
therefore a signal for the remodeling of the adipose tissue. (Adapted
from Ye J. Emerging role of adipose tissue hypoxia in obesity and insu-
lin resistance. Int J Obes [Lond] 33[1]:54-66, 2008.)
632 PART 5 DIABETES MELLITUS
in obesity without an adequate support of vasculariza-
tion might lead to hypoxia, macrophage infiltration, and
inflammation was confirmed in human studies66 (nicely
reviewed in reference 67).
Over the past few years, publications have provided
growing evidence suggesting that ER stress may also play
a role in the pathogenesis of type 2 diabetes.68 The ER is
a highly dynamic organelle with a central role in lipid and
protein biosynthesis. It produces the transmembrane pro-
teins and lipids for most cell organelles and is responsible
for the synthesis of almost all secreted proteins. After
the translation of proteins is performed by ribosomes on
the cytosolic surface of the ER, the unfolded polypeptide
chains are translocated into the ER lumen where numer-
ous chaperone proteins are crucial for the proper folding
of proteins and protein complexes.69
However, the ER is exquisitively sensitive to alterations
in homeostasis, and proteins formed in the ER may fail to
attain proper conformation due to: (1) lack of chaperones
or energy to promote chaperone-protein interactions, (2)
calcium depletion, (3) disruption of the redox state, (4)
protein mutations that hamper adequate folding, and (5)
reduction of disulfide bonds.68 ER stress is also called the
unfolded protein response (UPR). Lipotoxicity and glu-
cotoxicity as seen in prediabetes and diabetes are triggers
of ER stress.
Excess FFAs as seen in obesity activate the ER stress
response in beta cells, eventually causing apoptosis.70
Data suggests that hypoxia in adipose tissue of obese
mice and individuals may contribute to the induction of
ER stress and thereby affect adipokine production. For
example, adiponectin expression was decreased in adi-
pose tissue from high-fat–fed KKAy mice.71 Evidence for
the role of ER stress in human tissues such as pancreas,
muscle, and adipose is not currently available. Similarly,
increase in expression and phosphorylation of stress-
activated kinases such as p38 and JNK were detected
in omental adipose tissue from obese women compared
with lean controls.72 In the next few years, research in
this area should lead to a better understanding of the
interaction between obesity, inflammation, hypoxia, and
ER stress.
In addition to disordered FFA release, inflammation,
ER stress, and hypoxia, fibrosis may play a pathophysi-
ologic role in obesity.73 Initial studies in mice and later
in humans10,74-76 demonstrated upregulation of genes
encoding several collagens including collagen VI. Col-
lagen VI is particularly interesting, as the knockout
of COLVIα3 combined with the absence of the leptin
gene ob led to massive obesity and remarkable adipo-
cyte hypertrophy. In contrast to the degree of obesity
and hypertrophy, these animals were insulin sensitive
and metabolically normal. The hypertrophy suggested
that COLVIα3 acts as a “brake” on adipocyte growth.
Further study of the COLVIα3 protein revealed a novel
peptide fragment that they named endotrophin.77-78
Importantly, neutralizing antibodies directed to this
small peptide endotrophin normalized insulin action in
obese mice.79 This suggests that endotrophin is a key
autocrine, paracrine, or endocrine regulator of insulin
resistance in obesity.
Link Between Too Little Fat and Insulin Resistance
At the other end of the spectrum from obesity, it is now
recognized that a lack of adipose tissue is also associ-
ated with insulin resistance and increased risk for devel-
opment of type 2 diabetes. Lipodystrophy in humans is
an acquired or hereditary syndrome characterized by
decreased adipose tissue mass, insulin resistance, and
often diabetes mellitus.80-83 In these patients, insufficient
adipose tissue mass leads to excess energy storage as tri-
glycerides in liver and skeletal muscle and causes insu-
lin resistance in these tissues.84,85 Genetic manipulation
causing ablation of adipose tissue in mice supports the
link between adipose deficiency and insulin resistance.
Transgenic animals without adipose tissue store lipid in
skeletal muscle and liver and develop insulin resistance,
glucose intolerance, and eventually diabetes.86-88 This is
identical to the fatty liver and muscle seen in obesity and
type 2 diabetes. Furthermore, transplantation of adipose
tissue back into lipoatrophic animals reverses the elevated
glucose levels.89 However, transplantation of adipose tis-
sue from leptin-deficient mice (ob/ob) did not improve
the metabolic abnormalities, indicating that the seques-
tration of triglyceride into adipose tissue is not entirely
sufficient to restore insulin sensitivity.90 In humans, treat-
ment of lipodystrophic patients with leptin can dramati-
cally reverse the fatty liver and insulin resistance,91-93 and
recombinant leptin is now FDA approved for lipodystro-
phy.94 On the other hand, surgical removal of adipose
tissue causes metabolic syndrome.95 Together these stud-
ies demonstrate that, like in obesity, inadequate adipose
tissue mass leads to “ectopic” fat storage and metabolic
disturbances. Too little fat is therefore as deleterious
as too much fat and predisposes to the development of
the metabolic syndrome with insulin resistance and ulti-
mately type 2 diabetes. Three new paradigms may there-
fore explain insulin resistance as follows:
  
1. Inadequate lipid storage leading to “ectopic fat
storage syndrome” in which excess fat is deposited
in tissues other than adipose tissue with functional
disturbances in these tissues
2. “Endocrine adipocyte” that secretes increased
amounts of hormones involved in insulin resistance
and cardiovascular disease or secretes decreased
amounts of beneficial hormones such as adiponectin
3. Inflammatory, fibrotic adipose tissue with adipose
tissue macrophage infiltration and macrophage acti-
vation, leading to dysregulation of adipocyte lipid
metabolism and disordered adipokine secretion
  
Obesity is Another Ectopic Fat Storage Syndrome
Positive energy balance in our “obesigenic” environment
produces a pattern similar to lipodystrophy in humans,
that is, excess lipid storage in liver96 and skeletal mus-
cle25,97,98 followed by insulin resistance, glucose intoler-
ance, and diabetes. However, in contrast to lipodystrophic
patients, adipose tissue stores are adequate or even large
in obese patients, suggesting that the size of adipose tis-
sue becomes inadequate to sequester dietary lipid away
from liver, skeletal muscle, and pancreas. The adipocyte
 36 ROLE OF THE ADIPOCYTE IN METABOLISM AND ENDOCRINE FUNCTION 633

becomes hypertrophic and unable to recruit and/or differ-

entiate new adipocytes to store the excessive dietary fat.99
This hypothesis is supported by the fact that, indepen-
dent of total fat mass, individuals with larger abdominal
fat cells are at higher risk of developing type 2 diabetes
than individuals with smaller fat cells.100 Furthermore,
thiazolidinediones (TZDs) improve insulin resistance par-
tially by promoting differentiation of new fat cells in sub-
cutaneous adipose tissue through activation of PPAR-γ,
therefore providing extra storage capacity for dietary
fat.101,102 When driven by PPAR-γ agonists, adipogenesis
translates into a gain in subcutaneous adipose tissue103
and a decrease in lipid infiltration in skeletal muscle and
liver.104,105 Through the upregulation of genes in the lipid
storage and synthesis pathways in adipose tissue, TZDs
also decrease FFA, providing a second mechanism to pro-
tect liver, muscle, and the beta cell from fatty acids.106,108
As discussed later, drugs may therefore be designed to A
decrease ectopic fat storage by increasing adipogenesis
and/or increasing fat oxidation leading to improved insu-
lin action. Weight gain with PPAR-γ agonists in humans
is probably due to an increase in food intake consistent
with the action of the PPAR-γ agonists to increase food
intake.109-111
Adipose Tissue: Hypertrophy vs. Hyperplasia
Historically, adipose tissue was viewed as an inert tissue
with a singular function: lipid storage. The main areas of
research in the field of adipose tissue were related to adi-
pocyte size and number as well as lipid synthesis, adrener-
gic regulation of lipolysis, and insulin signaling in isolated
adipocytes. In adults, obesity is associated with an
increase in both the number and size of adipocytes112,113
(Fig. 36-4). The increase in fat cell size (hypertrophy) is
thought to reflect an imbalance between adipocyte lipid
uptake or synthesis and the release of lipid via lipolytic B
pathways. In addition to increased adipocyte size, obese
individuals have an increase in the absolute number of Figure 36-4 Hyperplastic versus hypertrophic obesity. Adipocytes are
derived from mesenchymal stem cell precursors (see Figure 36-7). Both
adipocytes (hyperplasia). Early studies demonstrated het- the mesenchymal precursors and the preadipocyte, whose differentia-
erogeneity in fat cell size; some obese patients have adipo- tion potential is limited to the adipocyte lineage, can undergo mitosis.
cytes as large as 1 μl, and others have very small fat cells. Hyperplastic obesity (A) is defined by an increase in the number of adi-
This heterogeneity led to the concept of hypertrophic or pocytes, while adipocyte size remains small. Hypertrophic obesity (B) is
characterized by larger adipocytes. The reason for the increase in adi-
hyperplastic obesity based on the average size of fat cells pocyte size is not clear. Current hypotheses suggest that a failure of the
(see Fig. 36-4). In contrast to this dichotomous viewpoint, large adipocyte to recruit preadipocytes to differentiate may play a role
the reality is that obese individuals cannot be grouped into in the development of insulin resistance, a precursor to overt beta cell
such simple categories. There is a continuous distribution failure as manifested by diabetes. (Photomicrographs courtesy of Prof.
Saverio Cinti, MD, Institute of Anatomy, Faculty of Medicine, Univer-
of fat cell size, and most obese patients have both hyper- sity of Ancona, Italy.)
trophy and hyperplasia. Increased fat cell size is positively
correlated with fasting insulin and negatively with insulin
sensitivity.114 In Pima Indians, increased abdominal adi- mass is the result of increased lipid storage in adipocytes.
pocyte size is associated with insulin resistance,100,115 a A second view is that fat cells can continually be recruited
potential inherited trait116 that predicts the onset of type to differentiate into mature lipid-storing fat cells, and
2 diabetes.100 Together, these data suggest that increased large fat cells are an indication of a failure of this process.
fat cell size is important to whole-body metabolism and Several investigators have proposed that once adipocytes
insulin action. are filled to a certain degree, new fat cells are “recruited,”
There are several ways of thinking about why fat cells and lipid is then stored in these new insulin-sensitive and
might be large in obese individuals. First, adult adipose tis- lipid-hungry adipocytes.117 The cross-sectional data used
sue has been viewed as a non-mitotic tissue, and increases to support this model is presented in Figure 36-5. Aver-
in adipocyte size might simply reflect an imbalance age fat cell size increases as body fatness increases up to
between storage and lipolysis. If the number of adipo- a certain point, after which increased adiposity does not
cytes is considered “fixed,” any increase in adipose tissue result in an increase in fat cell size. Even if individuals
634 PART 5 DIABETES MELLITUS

with hyperplastic or hypertrophic obesity lose weight
equally, hyperplastic obese patients regain the weight
much more quickly than hypertrophic subjects, lending
support for the concept of small lipid-hungry fat cells118
(Figure 36-6). During weight loss, fat cell size decreases
without a change in fat cell number but with a decrease
in fasting insulin.114 This has been interpreted as evidence
that once a fat cell is formed, it is permanent. However,
studies have demonstrated a relatively high rate of adi-
pocyte turnover119 and evidence for regulation of apop-
tosis.120 It should be noted that there is neither sufficient
longitudinal data nor sufficiently precise measures of fat
cell number to confirm this model in humans. This is in
part due to our current inability to accurately quantify the
number of stem cells and preadipocytes in adipose tissue
in vitro or in vivo, as well as the difficulties in quantify-
ing the very smallest fat cells in adipose tissue.121 Studies
using nuclear bomb–released 14C suggest that approxi-
mately 10% of fat cells are renewed annually.122
In contrast, the cross-sectional data illustrated in Fig-
ure 36-6 could also be interpreted as evidence for the
recruitment of new adipocytes. If fat cell hypertrophy

GROWTH AND DEVELOPMENT OF ADIPOSE TISSUE IN CHILDHOOD

Fat cell number

Fat cell size

1m 6m 12m 24m 48m 8y adult 1m 6m 12m 24m 48m 8y adult

A Age B Age

Figure 36-5 Schematic relationship between age, body fat mass, and fat cell size/number in childhood. A, Whole-body fat cell number remains
constant during the first year of life and then increases over time. There is a wide range of fat cell sizes and numbers across individuals as indicated
by the dashed lines. B, The increase in body fat that is seen during the first year of life occurs primarily as a result of increased lipid storage and
hypertrophy of existing adipocytes rather than through the recruitment of preadipocytes. (Data from Hager A, Sjostrom L, Arvidsson B, et al. Body
fat and adipose tissue cellularity in infants: a longitudinal study. Metabolism 26[6]:607-614, 1977; and Soriguer Escofet FJ, Esteva de Antonio I,
Tinahones FJ, Pareja A. Adipose tissue fatty acids and size and number of fat cells from birth to 9 years of age—a cross-sectional study in 96 boys.
Metabolism 45[11]:1395-1401, 1996.)

ADIPOSE TISSUE CELLULARITY AND CELL SIZE IN ADULTHOOD

Fat cell number

Fat cell size

A BMI or fat mass B BMI or fat mass

Figure 36-6 Schematic relationship between body fat mass and fat cell size/number in adulthood. A, In adults, whole-body fat cell number increases
with increasing body mass (hyperplasia). B, Again in adults, cross-sectional data shows a positive correlation between body fat mass and fat cell size
at lower body fat mass (solid line) until fat cell size reaches a plateau at higher levels of fat mass. At this point, fat cell size cannot increase any further
due to (a) limitations on lipid storage for unknown reasons, and/or (b) recruitment of existing preadipocytes to differentiate and store lipid, and/or
c) proliferation and differentiation of mesenchymal precursor cells into mature lipid-storing adipocytes. If fat cell proliferation, differentiation, and/
or recruitment did not occur, fat cell size would continue to increase as fat mass increased. There is a wide range of fat cell sizes and numbers across
individuals as indicated by the dashed lines. Fat cell number does not appear to change with weight gain or loss; however, precise tools are not avail-
able to quantify small changes in adipocyte number in vivo in humans. (Adapted from Hirsch J, Batchelor B. Adipose tissue cellularity in human
obesity. Clin Endocrinol Metab 5[2]:299-311, 1976.)
 36 ROLE OF THE ADIPOCYTE IN METABOLISM AND ENDOCRINE FUNCTION
was the only way to gain fat, then fat cell size would
increase linearly with fat mass. This is not the case. Based
on cross-sectional data, the point at which hypertrophy
recruits new fat cells probably occurs when average cell
volume reaches 0.8 to 1.0 μl.123-125 Two additional pieces
of evidence support the view that recruitment of new
fat cells occurs in vivo in humans. First, when adipose
tissue is separated into fat cells and the remaining cell
populations (stromal-vascular fraction), adipocytic pre-
cursor cells from the stromal-vascular fraction are able
to differentiate in vitro into mature lipid-storing adipo-
cytes throughout life and into old age. Obesity and age
are determinants of the capacity to differentiate adipo-
cytes in vitro.126,127 Studies of in vivo DNA synthesis in
humans suggest that adipocyte turnover is high in adult
humans, with a t½ ranging from 240 to 425 days.119,128
Other work suggests that the large fat cells secrete a factor
or factor(s) that promote adipocyte proliferation and dif-
ferentiation, a finding that is consistent with the recruit-
ment of “new” adipocytes by hypertrophic adipocytes, as
discussed earlier.129
Studies in rodents by Hirsch and colleagues demon-
strated that animals that were calorically deprived before
weaning had a reduced total number of fat cells when
compared to animals that were suckled in smaller lit-
ters with higher caloric intake. Similarly, about half of
the obesity in Zucker fatty rats can be prevented by the
early restriction of energy.130 This gave rise to the concept
that early overfeeding during adipose tissue development
might increase the population of adipocytes and their
precursors that produce obesity over time. This model,
known as the adipose-cell or critical period hypothesis,
predicts that a large number of adipocyte precursors early
in life could lead to the development of obesity by provid-
ing a “sink” destined to be filled with lipid. A corollary to
this concept is that individuals with a reduction in adipo-
cyte precursors (e.g., those with a failure of adipocyte dif-
ferentiation, described earlier) would be predisposed to
the development of diabetes when food intake is increased
as their storage capacity for excess fat is diminished.
Although the concept of an early-life “critical period”
for adipocyte precursor development has been much dis-
cussed, by comparison the actual data supporting this
concept is sparse. Consistent with this concept, obese
subjects with an early childhood onset of obesity tend to
have smaller fat cells and are less hyperplastic when com-
pared to those with a later adult onset of obesity.131,132
Similarly, children of mothers who were energy-deprived
during the Dutch famine of 1945 had a lower incidence
of obesity in adulthood.133 Although no prospective long-
term data exists to support the adipose-cell hypothesis,
the cross-sectional data supports the concept that in many
cases of early-onset obesity, adipose tissue size tends to be
hyperplastic rather than hypertrophic; the latter is more
often seen with late-onset obesity.
The original data and hypothesis presented by Hirsch
suggested a single early “critical period”; later discussions
offered the concept that additional critical periods of adi-
pocyte precursor proliferation might also exist113 with
recruitment from the precursor pools into mature adipo-
cytes throughout life. At birth, a typical infant has about
635
4 billion observable fat cells, and this increases to approx-
imately 10 to 40 billion in lean individuals and up to 50
to 100 billion in obese patients,134 supporting the concept
of ongoing adipocyte proliferation and/or recruitment
throughout life. In contrast to rodents, humans have a
long, slow growth and development period (neotony)
and are likely to have several critical periods of adipocyte
development.135
Body fat mass increases during the first year of life
mostly through fat cell hypertrophy. After the first year,
the number of adipocytes increases, the fat cell size
remains relatively constant, and whole-body adiposity
(% fat) decreases. At about 6 years of age, % body fat
begins to increase again. This has been termed the adi-
posity rebound. Longitudinal body weight data in chil-
dren demonstrates that an earlier adiposity rebound is
associated with obesity in adulthood.136-138 Although no
detailed information exists on the relative role of hyper-
trophy versus hyperplasia for this age range, the adiposity
rebound is considered a critical period for adiposity later
in life.139
Regulation of Adipogenesis
Adipose tissue, unlike other tissues such as the brain, kid-
ney, or liver, retains the ability to increase in size in adult-
hood. Several processes control the mass of adipose tissue
in the body as follows:
  
• A dipocyte precursor proliferation
• Differentiation of these precursors into mature,
insulin-sensitive, lipid-storing adipocytes
• The balance of lipid storage, utilization, and release
within each mature adipocyte
• Apoptosis of mature adipocytes
  
Adipocytes can be classified based on anatomic loca-
tion as subcutaneous, visceral (intraperitoneal), bone
marrow, and structural (periorbital, e.g., palms of hands
and soles of feet). The hereditary and acquired lipodys-
trophies teach us that each of these “depots” of adipose
tissue are developed or regulated differently, as each form
of lipodystrophy results in the loss or failure to differenti-
ate in specific depots. For example, in congenital gener-
alized lipodystrophy, “mechanical” adipose tissue of the
palms and soles is spared.140
Adipose tissue precursors are primarily mesenchymal in
origin (Figure 36-7). These precursor cells, also known as
preadipocyte or stromal cells, have the capacity to differ-
entiate into a limited number of cell types including adipo-
cytes, osteoblasts, and chondrocytes.141 There are at least
two distinct subtypes of preadipocytes [reviewed in refer-
ence 142]. These two subtypes, probably distinct from the
WAT/BAT “switch” described later, differ in their capac-
ity for replication, differentiation, and susceptibility for
TNFα-induced apoptosis. Subcutaneous adipose tissue
preadipocyte precursors replicate faster and differentiate
better than omental precursors. There is some evidence
that omental and mesenteric adipose tissue preadipocytes
differ as well.143-144 These differences in preadipocyte
characteristics are postulated to influence the propen-
sity of an individual to store fat in the visceral versus
636 PART 5 DIABETES MELLITUS
Pleuripotent Pre-adipocyte Mature insulin
precursor sensitive, lipid storing
(MSC) adipocyte
Protein/activity
C/EBP δ
Phospho-STAT5
C/EBP β
PPAR γ
C/EBP α
Days
PPAR γ Differentiation
C/EBP β
Adipocyte gene expression
C/EBP δ
C/EBP α Insulin sensitivity
Figure 36-7 Adipocyte differentiation cascade. Adipocytes are derived
from mesenchymal stem cell precursors (MSC). Both the mesenchymal
precursors and the preadipocyte, whose differentiation potential is lim-
ited to the adipocyte lineage, can undergo mitosis. The middle panel
depicts the coordinate, sequential activation of the major nuclear tran-
scription factors thought to be involved in the adipogenic differentiation
process. PPAR-γ is considered an obligatory “master” regulator of adi-
pogenesis. The PPAR-γ system turns on genes involved in lipid synthesis
and insulin action.
subcutaneous depots. Transcriptome analysis of subcuta-
neous and visceral adipose tissue revealed a distinct pat-
tern of expression of many genes, not only between depots
but also across BMI.145-146 In addition, there were major
differences in the expression of developmental genes in
subcutaneous versus visceral adipose tissue. Similarly,
gluteal-femoral subcutaneous adipocytes display a differ-
ent pattern of HOX genes, microRNAs, and long non-
coding RNAs,147,148 suggesting epigenetic control of the
known differences in the cell and tissue biology of upper
and lower body adipocytes.149-152 Taken together with the
cellular phenotypes identified by Kirkland’s laboratory,153
this suggests that the different cell types contribute to dif-
ferences in the function of each adipose tissue region and
that these differences can be explained by developmental
programming. In addition to these developments in the
different types of preadipocytes, the origins of the pre-
adipocyte are becoming clearer. Work in multiple tissues
including adipose tissue suggests that pericytes, cells that
lie just outside the capillary, are a major source of mesen-
chymal stem cells and preadipocytes.154-155
We know very little about the systems that control
proliferation of adipose tissue precursors. Most of what
we know is derived from the study of the cellularity of
rodent adipose tissue or the behavior of stromal-vascu-
lar cultures in vitro. Some of the known activators and
inhibitors of adipogenesis are presented in Table 36-1.
TABLE 36-1 Extracellular Factors That Regulate
Adipogenesis
Activating
• GH/IGF-1/insulin
• Cortisol (GR ligand)
• Thyroid hormone (TR ligand)
• Retinoic acids (RXR ligands)
• “Endogenous” PPAR-γ ligands
i. PGJ2
ii. HODEs/HETE
Inhibiting
• TNF-α
• IFN-γ
• Pref-1
• Resistin
• TGF-β
For example, IGF-1, a growth factor under the control of
insulin and growth hormone (GH) in adipose tissue, pro-
motes the proliferation and differentiation of preadipo-
cytes, while TGF inhibits proliferation.156 More is known
about the processes whereby adipocyte precursors, par-
ticularly 3T3-L1 preadipocytes, proceed along the path-
way from precursor to mature adipocyte. We now know
that a series of transcription factors coordinately regulate
multiple genes in a tightly regulated temporal fashion. As
shown in Figure 36-7, each of these transcription factors
forms a nonredundant network that, once initiated, leads
to the emergence of the adipocyte phenotype. Some of
the known “key” transcription factors include PPAR-γ;
STAT5; C/EBP/α, β, and δ; SREBP1c/ADD; CREB; and
Wnt/frizzled. In addition, a new family of proteins—the
Kruppel-like factors—has been identified as regulators of
adipocyte differentiation.157
Multiple hormones, cytokines, growth factors, cell
cycle regulators, and adhesion molecules control this dif-
ferentiation “cascade.” Classic studies by Green and col-
leagues showed that when clonal cell lines such as 3T3-L1
and F442A are confluent, they differentiate into adipo-
cytes if exposed to a cocktail of insulin, dexamethasone,
and isobutylmethylxanthine (IBMX).158-160 Emphasis has
also been placed on the role of cell cycle and the necessity
for proliferation prior to differentiation of precursors.
However, more recent data suggest that this has more to
do with the E2F transcription factors rather than the pro-
cess of mitosis per se.161-162
IBMX and other agents that increase cAMP act
through the transcription factor CREB.163 Several tran-
scription factors are critical for the conversion of cells
from a fibroblastic phenotype to an adipocytic pheno-
type. PPAR-γ has received the most attention, and this is
warranted since overexpression of PPAR-γ into fibroblas-
tic cell types is sufficient to confer the adipocytic pheno-
type.164 There are several putative “endogenous” ligands
for PPAR-γ including the prostaglandin PGJ2,165,166
long-chain fatty acids, and 13-HODE and 15-HETE,
which can be generated from linoleic and arachidonic
acids, respectively, by a 12/15-lipoxygenase.167 All of
these compounds can activate the PPAR-γ transcription
 36 ROLE OF THE ADIPOCYTE IN METABOLISM AND ENDOCRINE FUNCTION
factor that heterodimerizes with the RXR transcription
factor to turn on genes in the glucose uptake,168,169 lipid
uptake170 and lipid synthesis pathways.171,172 The true
endogenous ligand(s) are unknown, but their synthesis/
activity appears to be downstream of the C/EBP-β tran-
scription factor.173 C/EBP-α is expressed contempora-
neously with PPAR-γ and facilitates the full adipocytic
phenotype. Immediately upstream of PPAR-γ lies the C/
EBP transcription factors C/EBPβ and C/EBPδ, which
upregulate PPAR-γ. Other transcriptional promoters of
adipogenesis include STAT 5,174 the glucocorticoid recep-
tor, and ADD/SREBP-1c.175 Transcriptional inhibitors
include GATA 3,176 TCF/LEF, and the Wnt pathway.177
Combined with the transcriptional activators, they coop-
erate in an orchestrated cascade of transcriptional events
leading to a mature adipocyte.
Lastly, PPAR-γ cofactors may regulate the ultimate
transcriptional program in adipocytes. For example, adi-
pocytes can be converted from energy storage to energy
consumers by the PPAR-γ cofactor PGC-1a.178 Similarly,
the PPAR-γ cofactors SRC-1 and TIF2 may determine
the responses of adipose tissue to high-fat diets, SRC-1–
activating fatty acid oxidation, and TIF2-promoting lipid
storage.179 These two examples highlight a growing under-
standing that not only the ligand but also the transcrip-
tion factors and cofactors are important in whole-body
metabolism. The intracellular transcriptional control sys-
tem is regulated by extracellular signals from cytokines,
hormones, neural inputs, and the autocrine/paracrine pro-
duction of ligands for these transcription factors.
Adipocytes and indeed virtually all other cells store
neutral lipids, such as triglycerides, in droplets of varying
sizes. These droplets are formed as triglyceride is synthe-
sized in the ER or taken into the cell from the plasma
membrane. Lipid droplets are coated by a layer of phos-
pholipids and proteins that serve to sequester the neutral
lipids from the cytosol and to regulate the access of lipases
to the surface of the lipid droplet. Substantial progress has
been made in the identification of these lipid coat proteins
since the initial discovery of perilipin and other members
of the perilipin family (perilipin, adipophilin, S3-12, and
TIP-47).180 Consistent with their functional role, the
structure of these proteins is highly conserved with both
hydrophilic and hydrophobic domains. In adipose tis-
sue, each PAT protein plays a distinct role contributing
to lipid synthesis or lipolysis. For example, perilipin-A is
phosphorylated by PKA and PKG, which allows docking
of lipases and the initiation of lipolysis.181 On the synthe-
sis side, the repertoire of lipid droplet proteins changes as
the lipid droplet is formed and matures, demonstrating
the on-off exchange of these proteins and the dynamic
nature of the process for formation and movement of
lipid droplets. Once again, the biology shows that the adi-
pocyte is not a static, inert tissue but rather participates as
an active organ in the regulation of metabolism via lipid
droplets, which are dynamic organelles in their own right.
Lipid droplet proteins may also play an important role in
lipid oxidation independent of their role in lipolysis. A
novel PAT protein LDRP5 (also called OXPAT or Mldp)
appears to be important to activate lipid oxidation in oxi-
dative tissues such as the cardiac myocytes.182
637
Given their central role in lipid storage and synthesis,
the PAT proteins are being actively explored as a means
to better understand the regulation of these critical cel-
lular processes.
Brown Adipose Tissue in Humans
BAT is an exquisitely designed tissue/organ system
evolved for the maintenance of body temperature. It is
characterized by smaller cells with large amounts of mito-
chondria and small lipid droplets providing a potential for
high cellular metabolism. At the metabolic, protein, and
transcription levels, the BAT is upregulated principally
by the sympathetic nervous system when production of
heat is needed to maintain body temperature. Years ago,
Nicholls and Ricquier described a mechanism for heat
production based upon a specific highly abundant protein
(uncoupling protein 1; Ucp1) in the inner mitochondria
of the brown adipocytes that uncouples the production of
chemical energy as ATP from oxidative phosphorylation
and instead produces heat.183,184
Until quite recently, BAT has been thought to be
mostly important in small mammals and infants to main-
tain body temperature, but a function in the physiology
of adult humans was dismissed because of low numbers
of brown adipocytes.185,186 However, unrelated pursuits
in nuclear medicine using PET/CT scanning techniques
have revealed the presence of BAT in adult humans espe-
cially after cold exposure.187-188 The question is now how
can we induce this amazing organ not only to generate
heat but also to enhance fat oxidation, take up glucose,
and therefore reduce obesity.
Although the normal function of brown fat thermo-
genesis may be specific for the regulation of body temper-
ature, many genetic and pharmacologic studies in rodents
have shown that constitutive overexpression of Ucp1 in
white fat and skeletal muscle can drastically reduce both
genetic and diet-induced obesity, offering therefore a new
safe molecular target for the treatment of obesity.189-191
This potential for brown fat adaptive thermogenesis as
a drug target for obesity has not been ignored by the
pharmaceutical industry. Unfortunately, many candidate
agonists of the beta-3 adrenergic receptor have failed in
human clinical trials, even though these drugs have been
efficacious in rodent models of obesity. What is different
in the human and mouse?
Most of the effects of genetic, pharmaceutical or cold-
induced upregulation of Ucp1 in the mouse models result
in the emergence of new brown adipocytes in white fat
depots with levels of Ucp1 upregulated up to several
hundred fold (Figure 36-8). Unfortunately, human WAT
does not appear to be able to mount such transient induc-
tion of brown adipocytes, at least not in subcutaneous
adipose tissue. The failure of brown fat thermogenesis
in humans appears to be based upon the lack of funda-
mental information on the mechanisms controlling the
developmental origins of brown adipocytes in the discrete
brown fat depots (e.g., interscapular brown fat) and in
the small number of diffusely localized brown adipocytes
in various white fat depots. However, the transcription
factor PRDM16, whose presence can promote the dif-
ferentiation of preadipocytes and myoblasts into brown
638 PART 5 DIABETES MELLITUS

? BMP7
Mesenchymal stem cells

Preadipocyte Progenitor cell

In utero
? +PRDM16 PRDM16

Discrete BAT Skeletal

muscle
WAT
Post-natal
Adrenergic
signaling
Neck
Supraclavicular
Diffuse BAT
Mediastinum
(para-aortic)
Paravertebral

?
Suprarenal

Figure 36-8 Brown adipose tissue in humans. Mesenchymal stem cells can have two major pathways, one into preadipocytes and another into
progenitor cells of brown adipocytes or skeletal muscle cells. Bone morphorgenetic protein 7 (BMP7) activates a full program of brown adipogenesis
including induction of early regulators of brown fat PRDM16 and PGC-1α. In absence of PRDM16, these progenitor cells are transformed into
skeletal muscle cells. Preadipocytes are differentiated into white adipocytes in subcutaneous and visceral adipose tissue. By stimulation of adrenergic
signaling, some of these white adipocytes can be transformed into brown adipocytes defused in the white adipose tissue (WAT). On the other hand,
discrete brown adipoctyes are concentrated in brown adipose tissue (BAT) depots such as in the neck, supraclavicular, paravertebral, and s­ uprarenal.
The BAT regulator PRDM16 is responsible, at least in rodents, only for the generation of discrete BAT. (From Seale P, Bjork B, Yang W, et al.
PRDM16 controls a brown fat/skeletal muscle switch. Nature 454[7207]:961-967, 2008; and Tseng YH, Kokkotou E, Schulz TJ, et al. New role of
bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454[7207]:1000-1004, 2008.)

adipocytes and whose absence promotes the myogenic
differentiation program192 (see Figure 36-8), plays a key
role in the development of BAT. Importantly, the abil-
ity of PRDM16 to induce the brown adipocyte lineage is
restricted to the discrete brown fat depots, such as that
found in the interscapular and supraclavicular region,
but it does not participate in the induction of the dif-
fuse brown adipocytes located in the white fat depots.
The data support the concept that interscapular BAT and
brown adipocytes in white fat have separate independent
developmental origins.193 PRDM16 is clearly an impor-
tant player in brown adipogenesis but may not be suf-
ficient, since PRDM16 KO mice have significant levels
of interscapular fat with Ucp1 expression.192 However,
one does not know whether upregulation of PRDM16 in
humans can induce increased discrete BAT and/or diffuse
brown adipocytes.
While the regulator PRDM16 has provided important
insights into the developmental origins of discrete brown
fat depots, the next important step will be to determine
the origin(s) of diffusely localized brown adipocytes in
white fat depots since at least in rodents. Diffuse BAT
adipogenesis is more closely related to increased ther-
mogenesis and with reduced obesity.146 Enthusiasm
for the promise of PRDM16 as a drug target needs to
be tempered by the caveat that mice with an inactivated
PRDM16 gene die at birth, suggesting that PRDM16 is
a transcription factor with additional unknown functions
in mammalian development. It has long been known
that chronic increases in circulating catecholamines in
patients with pheochromocytoma lead to large brown
fat depots.194 This historical data together with the more
recent findings of discrete brown fat depots uncovered by
PET technologies187 should stimulate a renewed effort to
find strategies to induce more brown adipocytes and to
ask why the many previous studies with beta-3 agonists
failed to significantly stimulate thermogenesis in humans.
Maybe the lack of beta-3 adrenergic receptors in human
white adipocytes is something that needs to be overcome
to facilitate conversion of white to BAT and to stimulate
thermogenesis. It is important also to evaluate the effects
of bone morphogenetic protein 7 (BMP7) on stimulating
 36 ROLE OF THE ADIPOCYTE IN METABOLISM AND ENDOCRINE FUNCTION
the enhanced expression of brown adipocytes as shown
by Tseng and colleagues in 2008.195 Similarly, the natri-
uretic peptides also stimulate the expansion and activa-
tion of BAT.196 Natriuretic peptides are released during
exercise, activate adipocyte lipolysis197 and therefore fat
oxidation,198 and when infused into humans increase
thermogenesis.199 Combined with the newly discovered
capacity for BAT activation and interaction with the
beta-3 adrenoreceptor, natriuretic peptides therefore pro-
vide an attractive target for reversing metabolic distur-
bances of obesity. Lastly, the neuropeptide orexin-A has
been shown in mice to expand and active BAT200 and is
necessary for BAT development. Irisin,201-203 metorin,204
and FGF-21205,206 are other key peptides in the regulation
of BAT mass and activity, the latter in a paracrine and
endocrine system involving the sympathetic nervous sys-
tem. Together, these results raise the intriguing possibility
that BAT might be activated pharmacologically through
non-adrenergic peptides such as orexin-A, irisin, FGF-21,
and the natriuretic peptides.
Since the reemergence of BAT as a potential player in
the regulation of energy homeostasis, there has been a
lingering question regarding the absolute effects in terms
of calories that can be burned by the small amount of
BAT in humans. Recent studies using chronic cold to acti-
vate BAT, analogous to using physical exercise to train
muscle, showed that BAT can be expanded and activated
in vivo in humans.207,208 The overall thermogenic capac-
ity appears to be between 100 and 300 kcal/day,209-211
although much work remains to be done to confirm
this.212
The discovery of previously uncovered BAT/cells in
adult humans and its potential physiologic significance in
cold- and dietary-induced thermogenesis should revamp
our effort to target the molecular development of brown
adipogenesis in the treatment of obesity.
Integrative Biology of the Adipose Tissue
To maintain energy homeostasis, the brain has two ave-
nues of communication with the periphery, hormones,
and neurons. The adipose tissue is no exception to this
rule, since it is well established that both hormones and
neurons control its life cycle and metabolism. Under-
standing how adipose tissue operates and is regulated
in vivo is a prime example of integrative biology. Imaging
studies of the different adipose depots as well as studies
of adipose tissue metabolism and secretary function using
arterial-venous differences and microdialysis in conjunc-
tion with measures of adipose tissue blood flow have all
improved our integrative view of the metabolism and
function of the adipose tissue.
There is increasing appreciation for the importance of
the vasculature to the proper functioning of the adipose
tissue. Nutrients such as glucose, fatty acids, and proteins
are supplied from the vasculature and are critical to the
growth and maintenance of adipose tissue. Recent studies
have focused on the supply of oxygen for oxidative metab-
olism in adipocytes. Current data suggest that the delivery
of oxygen may be limiting in adipose tissue of obese mice.
The consequences of the hypoxia are unclear, but in vitro
data59 support the in vivo data,63 suggesting that hypoxia
639
leads to chemotaxis of macrophages and inflammation.
These findings were recapitulated in human adipose tis-
sue.66 Under these circumstances, hypoxia should turn
on the transcription factor HIF-1 leading to angiogenesis
and a reversal of the hypoxia. This does not appear to be
the case in mature adipose tissue,213,214 where VEGF, a
primary downstream transcriptional target of the HIF-1
pO2 sensing system, is not activated. Anatomically, there
is good evidence that the new blood vessels sprout from
existing endothelial cells,215 and this has been co-opted in
the development of ex vivo assays to clearly demonstrate
that human adipose tissue is capable of sprouting/angio-
genesis.216 Why the angiogenic signals are not increased
when pO2 is decreased is a paradox that needs to be
investigated.
In murine adipose tissue development, angiogenesis,
adipogenesis and the stromal cells interact in a way that is
coordinated217,218 and relies on VEGF.219 This is different
from the situation in mature “hypoxic” adipose tissue,
highlighting the differences in mechanisms and the rela-
tive importance of growth factors in growth and devel-
opment as opposed to the events occurring in mature
adipose tissue. Adiponectin, secreted by small but not
hypertrophic inflammatory adipocytes, stimulates angio-
genesis, highlighting an interplay of adipokines, which
we typically consider a “metabolic” hormone working in
concert with the growth factors classically implicated in
angiogenesis.220
Endocrine Signals
Glucocorticoids
Glucocorticoid treatment of laboratory animals results
in the development of obesity. Animal models of obesity
invariably have increased levels of corticosterone. Adre-
nalectomy results in the reversal or prevention of obesity.
Activation of the glucocorticoid receptor results in dif-
ferentiation of preadipocyte precursors158-160 and lipid
storage in adipocytes. In humans, overproduction of
cortisol (Cushing’s syndrome) results in a phenotype of
central (abdominal) obesity, hypertension, and diabetes.
Of the many investigations into the role of adrenal gluco-
corticoids in human obesity, most show normal urinary
free cortisol, normal circadian variation in cortisol val-
ues, and normal plasma cortisol values, although meta-
bolic clearance rate and production are increased.221 The
enzyme 11βHSD-1 is present in human adipose tissue and
converts inactive cortisone into active cortisol.222 Impor-
tantly, there is a strong positive correlation between
adipocyte size and the activity of 11βHSD-1 to convert
cortisone into cortisol. This fits with the idea that adipo-
cyte hypertrophy generates signals, like cortisol, to recruit
new adipocytes.
The most compelling data for an association between
human obesity and cortisol comes from studies that clas-
sify obese women into central and peripheral types of
obesity. By stratifying volunteers on this basis, Marin and
coworkers demonstrated an increase in urinary and serum
cortisol as the waist-to-hip ratio increased.223 Serum cor-
tisol responses to stress were greater in women with high
waist-to-hip ratio, suggesting a role of response to envi-
ronmental stressors as a potential factor in abdominal
640 PART 5 DIABETES MELLITUS
obesity.223,224 Other evidence in humans suggests that
cortisol values within normal concentrations are some-
times related to fat patterning, possibly via increased sen-
sitivity to exogenous stressors. Genetic factors may also
determine the susceptibility of the adipose tissue to these
exogenous stressors.225
Growth Hormone/IGF-1
GH is a potent lipolytic hormone.226 GH receptors acti-
vate classic cAMP lipolytic systems in adipose tissue. In
addition to stimulating lipolysis, GH increases IGF-1
production in adipose tissue.227 IGF-1 potently activates
preadipocyte proliferation and differentiation of precur-
sors into mature lipid-storing adipocytes.156 Deficiency of
GH is associated with central obesity, and replacement of
GH reduces visceral adiposity.228 Despite early reports of
therapeutic efficacy of GH in men with central obesity,229
other studies do not show this effect and in fact show
an increase in body fat after GH withdrawal compat-
ible with the effects of IGF-1 to promote adipoctye dif-
ferentiation.213 GH treatment in the absence of clear-cut
GH deficiency cannot be recommended as the side-effect
profile includes edema, carpal tunnel syndrome, glucose
intolerance, and many others. GH-like peptides that
increase lipolysis without upregulation of IGF-1 synthesis
have been discovered230 and may be beneficial without
the adverse effects of GH.
Estrogen in Adipose Tissue
Men and women have a different distribution of body
fat: a gluteal-femoral pattern in women and an abdomi-
nal pattern in men. This sexual dimorphism is thought
to be due to differences in the sex steroids estrogen and
testosterone. Lipoprotein lipase (LPL) activity, indicative
of lipid storage, is increased in the gluteal-femoral region
of women as compared to men. After menopause, LPL
activity is equivalent across all adipose tissue depots, sug-
gesting that estrogen upregulates LPL in a depot-specific
fashion.231 In support of this concept, treatment of post-
menopausal women with estradiol increased LPL activity
in the gluteal-femoral region,232 which was reversed by
the addition of a progestin.233 In vitro in human abdomi-
nal subcutaneous adipocytes, low-dose estradiol increased
LPL protein, and higher-dose estradiol decreased LPL.234
These dose-dependent effects of estradiol to decrease LPL
were also observed in a cross-sectional study235 and after
local transdermal application of estradiol.236 In addi-
tion to systemic estradiol, the stromal-vascular fraction
of adipose tissue is able to convert estrogenic precursors
to estrogen vis-à-vis the enzyme aromatase. In men, tes-
tosterone, but not the non-aromatizable steroid dihy-
drotestosterone, increases adipose tissue lipid turnover,
suggesting that testosterone acts in adipose tissue via
local conversion of testosterone into estrogen by aroma-
tase.237,238 In vitro, estradiol increases the proliferation
of stromal-vascular cell cultures of both human 239 and
rodent preadipocytes.240
Several investigators241-244 have demonstrated estradiol
binding and ERα mRNA in adipose tissue extracts. After
the cloning of the ERβ gene, both mRNA and protein for
ERβ were subsequently described in adipose tissue.243-245
In human adipose tissue, ERβ was higher in abdominal
compared to gluteal femoral adipose tissue, and regional
differences in adipose tissue expression of ERα and ERβ
were described by Pedersen and colleagues.246 But not all
of the effects of estrogen are in the adipose tissue. Admin-
istering estrogen directly into the brain is able to reverse
the gain in visceral fat seen with ovariectomy, suggesting
that much of the fat patterning attributed to peripheral
effects might actually be mediated through hypothalamic
signaling.247
In summary, estradiol is an important sex steroid, both
for the proliferation of adipocyte precursors and for the
regulation of lipid storage in a regional-specific fashion.
Neural Signals to the Adipose Tissue
As discussed earlier, the human adipose tissue can be
divided into two major compartments, subcutaneous and
visceral (approximately 80% and 10%, respectively),
whereas other depots such as intramuscular adipose tis-
sue and retroperitoneal, perirenal, and orbital fat account
for the remainder.248 The two major compartments
have clearly different rates of lipid synthesis and lipoly-
sis, probably due to differences in hormonal exposure
and innervation. The brain needs to transmit messages
to different parts of the body in a selective manner. For
that reason, the sympathetic nervous system innervates
different adipose tissues in different ways, influencing
not only regional blood flow but also functions such as
lipolysis and lipid synthesis. By viral injection in fat pads
of Siberian hamsters, Youngstrom and Bartness showed
the presence of sympathetic projections from central sym-
pathetic ganglia, which were confirmed by injection of
fluorescent anterograde tract tracers into the sympathetic
chain ganglia249 and viral tracing studies.250-252 In addi-
tion, denervated fat depots weigh 10% more than the
intact contralateral depot, implying impaired lipid mobi-
lization in fat pads deprived of their innervation.253 From
such studies, it was hypothesized that catecholamines
not only increase lipolysis but also inhibit adipose tissue
hyperplasia from preadipocytes, which is supported by
in vitro data.250,254,255
Regulation of Lipolysis
Adipose tissue lipolysis, that is, the catabolic process
leading to the breakdown of triglycerides into fatty acids
and glycerol, is often considered as a simple and well-
understood metabolic pathway (Figure 36-9). However,
we continue to discover new layers of complexity in the
system. Hormone-sensitive lipase is a major determinant
of fatty acid mobilization in adipose tissue. Transloca-
tion of hormone-sensitive lipase to the lipid droplet seems
to be an important step during lipolytic activation. Reor-
ganization of the lipid droplet coating by perilipin may
also facilitate the access of the enzyme. In humans, altera-
tions of hormone-sensitive lipase expression are associ-
ated with changes in lipolysis in various physiologic
and pathologic states. The major hormones controlling
the lipolytic process are catecholamines (stimulation of
lipolysis) and insulin (inhibition of lipolysis). It is well
accepted that the adrenergic system is the major regulator
of lipolysis via a cAMP pathway. In turn, cAMP increases
 36 ROLE OF THE ADIPOCYTE IN METABOLISM AND ENDOCRINE FUNCTION
α2-agonists
Adenosine
NPY/PYY Insulin ANP
Norepinephrine Prostaglandins BNP
Rs Ri
Plasma membrane
Gs Gi
PDE3 GMP
ATP
AC
cAMP 5'AMP PDE5 GC GTP
cGMP
P-perilipin
Perilipin cAMP cGMP Perilipin
PrK PrK
Cgi-58 HSL P-HSL HSL
(PKA) (cGKI)
ATG
Cgi-58
LIPOLYSIS
Figure 36-9 Regulators of human adipocyte lipolysis. Hormone-sen-
sitive lipase and perilipin are rate-limiting steps in the regulation of adi-
pocyte lipolysis. Both enzymes need to be phosphorylated to be active
and allow the breakdown of triglycerides into glycerol and free fatty
acid. Part of this process involves the release of Cgi-58 when perilipin
is phosphorylated; it can then bind and activate ATGL, the specific tri-
glyceride hydrolase. The adrenergic systems (β-receptors and α2 recep-
tors) are major regulators of lipolysis via cyclic AMP (cAMP) pathways.
β-receptors stimulate lipolysis, whereas α-2 receptors inhibit lipolysis.
There are other novel Gi-coupled G protein–coupled receptors; see text
for details. cAMP increases the activity of protein kinase A, which in
turn phosphorylates the hormone-sensitive lipase and perilipin. Insulin
inhibits lipolysis via inhibition of phosphodiesterase (PDE), therefore
decreasing cAMP and lipolysis. A novel lipolytic system using natriuret-
ic peptides stimulates lipolysis through a cGMP-dependent pathway,
which is not influenced or suppressed by insulin action. In adipose tis-
sue, cGMP is degraded by PDE5 (385). AC, Adenlyate cyclase; AMP,
adenosine monophosphate; ANP, atrial natriuretic protein; ATGL,
adipose triglyceride lipase; BNP, brain natriuretic protein; cAMP, cyclic
AMP; cGMP, cyclic GMP; GC, guanylate cyclase; Gi, inhibitory G-protein;
GMP, guanine monophosphate; Gs, stimulatory G-protein; NPY/PYY,
neuropeptide Y, peptide YY; PDE, phosphodiesterase; Ri, receptor,
inhibitory; Rs, receptor, stimulating. (From Moro C, Klimcakova E,
Lafontan M, et al. Phosphodiesterase-5A and neutral endopeptidase
activities in human adipocytes do not control atrial natriuretic peptide-
mediated lipolysis. Br J Pharmacol 152[7]:1102-1110, 2007.)
the activity of protein kinase-A, which phosphorylates
both the hormone-sensitive lipase and perilipin. As a
counteracting hormone, insulin binds to its receptor and
activates the various elements of the insulin signaling
cascade by stimulation of Type 3 cGMP-inhibited phos-
phodiesterase (PDE3B), therefore decreasing cAMP and
suppressing lipolysis.256 The antilipolytic effect of insu-
lin is reduced in the insulin-resistant state.257 Progress on
the hormonal regulation and molecular mechanisms of
beta-lipolytic and alpha2-antilipolytic adrenergic control
of lipolysis has improved our understanding of the rela-
tive contribution of the two types of receptors.258 Genetic
studies show that polymorphisms in genes coding for dif-
ferent beta-adrenoceptor subtypes and hormone-sensitive
lipase may participate in the polygenic background of
obesity.259
More recently, a novel lipolytic system has been char-
acterized in human fat cells. Natriuretic peptides stimulate
lipolysis through a cGMP-dependent pathway, which is
not influenced or suppressed by insulin action.260-262 Along
with catecholamine stimulation of cAMP, natriuretic
641
peptide activation of the cGMP system plays an important
role in exercise-activated lipolysis.197
It was once thought that hormone-sensitive lipase was
the first step in the lipolytic cascade. The recent discovery
of patatin-like phospholipase domain containing 2, also
known as Adipose TriGlyceride Lipase (ATGL), changed
that view, and we now know that ATGL is a key molecule
for the first step in triglyceride hydrolysis, TAG hydrolase
activity.263 ATGL and its co-activator protein CGi-58/
ABHD5 are required for the full activation of the lipolytic
cascade (see Figure 36-9), with HSL acting to hydrolyze
DAGs into MAGs and monoglyceride lipase finishing the
cascade. New data show that this sequential model may
be too simplified. When perilipin-A is phosphorylated
by PKA, CGi-58 is released and “assists” in the recruit-
ment of ATGL to the lipid droplet.264 Taken together,
the discovery of ATGL, along with the discovery of the
natriuretic peptide–driven cGMP lipolytic pathway,262
has dramatically changed our view of the regulation of
lipolysis. We now know that translocation of HSL to the
lipid droplet is not the only regulatory step in the activa-
tion of lipolysis; there is a network of controlled signal-
ing that includes interactions between the lipases and the
PAT proteins. This is a hot area of research, and a better
understanding of the interactions between the PAT pro-
teins, lipases, and their signaling systems will hopefully
lead to new therapies to prevent the dysregulated lipolysis
observed in hypertrophic adipocytes.
Adipocyte as an Endocrine Organ
The study of the biology of adipose tissue including the
mechanisms of adipogenesis has enjoyed an explosive
growth over the past 15 years. Unarguably, the trigger
for this renewed interest came from the cloning of the ob
(obese) gene and the discovery of leptin in 1994.2 This
seminal discovery initiated a period of intense research
for uncovering the endocrine and paracrine roles of the
adipose tissue and its role in the regulation of energy bal-
ance and the development of obesity and its related dis-
eases. The steps that led to the discovery of leptin were
summarized in the original description of the cloning of
the leptin gene.2 In brief, the original notion of a homeo-
static regulation of energy balance (and therefore adipose
mass) dates back to Lavoisier and Laplace.265-267 The key
role of the brain in this regulation came later from clini-
cal observations and was confirmed by stereotaxic lesions
of different regions of the brain.268 It was therefore pos-
tulated that energy balance was regulated by a feedback
loop in which the body energy stores were sensed by the
hypothalamus, which, in turn, sent signals to control
both food intake and energy expenditure. The nature
of the signal inputs to the hypothalamus was, however,
not clear. Jean Mayer proposed a “glucostatic theory” in
which blood glucose was the sensed signal.269 Kennedy
postulated the presence of a “fat metabolism factor”
and proposed what is now accepted as the lipostatic the-
ory.270 In this model, a signal coming from the fat stores
in the adipose tissue is read by the central nervous system
to regulate feeding and energy homeostasis. Subsequent
parabiosis studies performed by Hervey confirmed that
blood-borne signals were coming from the adipose tissue
642 PART 5 DIABETES MELLITUS
and regulated food intake and body weight.271 Not too
long after, Coleman performed the seminal parabiosis
studies using single-gene models of obesity and diabetes
(ob/ob and db/db mice) and concluded that the product
of the ob gene was secreted by the adipose tissue, trans-
ported by the blood, and received in the hypothalamus by
the receptor encoded by the db gene.272 This interaction
between a factor produced by the adipose tissue and a
receptor in the hypothalamus became the foundation for
Leibel and colleagues to undertake the positioning clon-
ing effort of the ob and db genes, leading to the publica-
tion of the discovery of leptin in Nature in 19942 and of
its receptor in Cell 1 year later.273
Since the discovery of leptin, the simple paradigm of
adipose tissue as a fat-storage tank has evolved into a
complex paradigm. First, the size of the adipose tissue
is not only controlled by the filling of pre-existing adi-
pocytes but involves finely tuned mechanisms control-
ling differentiation and apoptosis of the tissue. Second,
adipose tissue depots are multipotential secretory organs
with different secretory capacities for different depots.
These adipose tissues are composed mostly of adipocytes
but also of fibroblasts and immune cells such as macro-
phages and mast cells, which all use endocrine, paracrine,
and autocrine pathways to secrete multiple bioactive
proteins called adipokines or adipocytokines. The adipo-
cytes respond to various stimuli such as circulating hor-
mones, circulating metabolites, neural input, and cellular
energy signals by releasing hormones and substrates as
shown in Figure 36-10.274-275 The molecular revolution
brought to light many adipocyte-secreted factors, some of
which are secreted into the bloodstream such as IL-6 and
leptin, whereas others, such as TNF-α, exert their effects
in an autocrine/paracrine fashion.276 Although adipose
tissue has a similar histological appearance throughout
the body, it is now obvious that there are fundamental
regional differences in the quality and the amount of
secreted adipokines by these different depots.
A major emphasis in adipose tissue biology research
is the understanding of the molecular mechanisms con-
trolling the secretion of adipokines by different depots
and their implication in a variety of chronic diseases.
These secreted proteins have been grouped in molecules
regulating physiologic and pathophysiologic functions
­ stores become insufficient, commanding the body to seek
such as:275
  
1. Energy homeostasis (leptin, adiponectin, resistin,
omentin, apelin)
2. Innate immune system (TNF-α, IL-6, IL-8)
3. Vasculature (VEGF, monobutyrin, ESM-1)
4. Acute phase reactant response (alpha1 acid glyco-
protein, SAA3, PTX-3)
5. Molecules involved in lipoprotein metabolism/insu-
lin action such as LPL or components of extracel-
lular matrix (type VI collagen)
6. Recruitment of immune cells (MCP-1, MIP-1)
  
In this chapter, we have chosen to present the cur-
rent knowledge on only five of these adipokines: leptin,
adiponectin, resistin, TNF-α, and apelin. As shown in
­Figure 36-11, these adipokines are involved in whole-body
TNF-α
Interleukins
TGF β
IGF-1 FGF
Bone morphogenic protein IGFBP EGF
MCP-1
Fatty acids
Visfatin Lysophospholipid
Lactate
Resistin Adenosine
Adipose
Apelin Prostaglandins
Glutamine
Adiponectin Adipose
UNKNOWN
tissue
Adipsin FACTORS
Estrogen Agouti protein
Retinol
Angiotensin-II
Plasminogen activator
inhibitor-1
Angiotensin Leptin
Acylation-stimulating protein
Figure 36-10 Proteins secreted by the adipose tissue. Adipose tissue
is an endocrine gland that secretes numerous factors, many of which
are implicated in affecting energy homeostasis, insulin sensitivity, and
nutrient-sensing pathways.
metabolism since they act on different tissues including the
brain, the liver, the skeletal muscle, and the adipose tissue
itself.
Leptin
Leptin is a highly conserved 16-kD hormone secreted
principally but not exclusively by adipocytes and which
acts both centrally and peripherally. Plasma leptin con-
centrations are positively correlated with body fat
mass.277 Leptin crosses the blood-brain barrier by a satu-
rable active transport system and serves as a signal to the
central nervous system originating in the adipose tissue.
Even though it was originally described as the hormone
regulating energy balance, available data now suggest
that a relative lack of leptin or resistance to its action are
probably not causal of most cases of human obesity. The
main biological function of leptin seems to be the mainte-
nance of a minimum level of energy stores during periods
of caloric restriction.278-279 Low leptin concentration can
therefore be seen as a “starvation signal” when energy
food and become thrifty. As part of such a protective
mechanism, leptin plays a role in reproduction, angiogen-
esis, bone architecture, and immune function, and it may
also influence processes such as beta-cell insulin secre-
tion, carbohydrate transport, and platelet aggregation.280
Low levels of circulating leptin trigger strong biological
responses to protect the organism against the deleterious
effect of starvation, whereas high levels of leptin (as seen
in obesity) engender rather weak biological responses.278
This asymmetric biological effect of leptin is illustrated in
the upper panel of Figure 36-12.
Studies of caloric restriction in animals and humans
provide information regarding the importance of leptin
as a mediator of neuroendocrine responses. Shimokawa
reviewed the endocrine changes associated with short-
term caloric deprivation in rodent models.281 Many of
these alterations have been described in humans as well
 36 ROLE OF THE ADIPOCYTE IN METABOLISM AND ENDOCRINE FUNCTION 643

↓ Food intake
↑ Energy expenditure ↑ Triglyceride content
↑ Glucose output

↑ Insulin resistance
↑ Lipolysis
TNFα

Leptin

Free-fatty acids

Adiponectin ↓

Adipose tissue
Resistin

↑ Triglyceride content
↓ Glucose uptake

Figure 36-11 Central role of adipose tissue in insulin-resistant syndrome. The production by adipocytes of substrates such as free fatty acids; hor-
mones such as leptin, adiponectin, and resistin; and cytokines such as TNF-α positions the adipocyte as a central mediator of insulin-resistant syn-
drome in obese individuals. In response to weight gain, free-fatty acids, leptin, resistin, and TNF-α are all increased, whereas adiponectin concentra-
tion is decreased. These changes impact the insulin sensitivity of skeletal muscle and liver and the central nervous system control of energy expenditure
and food intake. Positive feedbacks are shown in solid lines, whereas negative feedbacks are shown in dotted lines. (Adapted from Farmer SR. In:
Alberti KGM, DeFronzo RA, Keen H, Zimmet P, eds. International textbook of diabetes mellitus. 3rd ed. Hoboken, NJ: John Wiley & Sons, 2004.)

and include a decrease in T3,282 an increase in cortisol
secretion,283 and a decrease in gonadal function.279 It has
long been hypothesized that the neuroendocrine system
coordinates and integrates some of the antiaging actions
of calorie restriction.284-287 In a 48-hour prolonged star-
vation study in mice, Ahima and associates provided evi-
dence that the reduction in leptin with starvation caused
a decrease in the activity of the gonadal and thyroid axes
and an increase in the activity of the adrenal axis.279 The
changes in activity of these axes during fasting were pre-
vented by leptin administration, suggesting that leptin is a
master regulator of the neuroendocrine system and possi-
bly the endocrine candidate of the “disposable soma the-
ory” of aging stating that longevity requires investment in
somatic maintenance by reducing the resources available
for reproduction281-288 (see Fig. 36-12, bottom panel).
In the obese state in which the circulating leptin con-
centration is already high (see Fig. 36-12), the hormone
is a rather weak signal to prevent overconsumption of
food and does not appear to be a viable treatment for
obesity.289 However, if provided in sufficient amounts
in obese individuals or to organisms deficient in circu-
lating leptin, injection of the hormone can reduce body
weight and fat mass by decreasing food intake and
increasing energy expenditure. The mechanism by which
leptin seems to exert its peripheral metabolic effects is
by activating 5′-AMP-activated protein kinase (AMPK)
in muscle and liver.290-291 As a consequence of AMPK
activation, ATP-consuming anabolic pathways are inhib-
ited, whereas ATP-producing catabolic pathways are
activated. The activated mechanisms include glucose
transport, beta-oxidation, glycolysis, and mitochondrial
biogenesis. The relevance of leptin in normal human
metabolic function is provided by leptin replacement in
individuals with genetic leptin deficiency,292 deficiency
due to weight loss,293 or lipodystrophy.294 The effects
of recombinant leptin therapy in children with congeni-
tal leptin deficiency was investigated and clearly showed
a spectacular effect on reducing food intake and body
weight but almost no effect on energy expenditure and
fat oxidation.292 In adult patients with a similar congeni-
tal deficiency, leptin replacement not only impacted food
intake but also prevented the drop in energy expenditure
usually observed with weight loss and increased 24-hour
fat oxidation by more than three times.295 Interestingly,
weight loss seems to be amplified in a synergetic manner
when leptin is administered in conjunction with pramlint-
ide, an analogue of amylin.296
HIV and HIV therapy are also associated with altera-
tions in body composition, including lipoatrophy, lipid
644 PART 5 DIABETES MELLITUS
Biological effect of leptin
Asymmetrical
biological response
A Plasma leptin concentration or body fat (%)
Energy restriction
↓Fat mass
↓Leptin
↑Energy available for: ↓Energy available for:
• Maintenance of soma • Reproduction
• Adrenalcortical axis • Growth
B • Energy metabolism
Figure 36-12 Leptin as the master neuroendocrine signal. As shown in
panel A, the biological responses to changes in body energy stores and
circulating leptin are asymmetric and are much more robust when plas-
ma leptin concentration decreases with caloric restriction and significant
weight loss rather than when it increases with obesity (278). Leptin’s
main function may be to provide the appropriate metabolic responses
to decreased energy stores (by acting to increase feeding and by sparing
energy/fat expenditure) rather than protecting the body against excess
energy stores (i.e., by increasing energy/fat expenditure and decreasing
food intake). Panel B describes the role of leptin as a master regula-
tor of neuroendocrine pathways involved in response to the effects of
caloric restriction. It is probably a major signal for the antiaging effects
of dietary restriction (281). (From Leibel RL. The role of leptin in the
control of body weight. Nutr Rev [10 Pt 260]:S15-S19, 2002; discussion
S68-S84, 85-17; and Shimokawa I, Higami Y. Leptin and anti-aging
action of caloric restriction. J Nutr Health Aging 5[1]:43-48, 2001.)
storage as abdominal adipose tissue, or buffalo hump.297
The constellation of metabolic findings in these patients is
consistent with the ectopic fat storage hypothesis as pre-
sented earlier. Several studies suggest that activation and
rebound of the immune system during antiretroviral ther-
apy are associated with lipodystrophy.298,299 This is anal-
ogous to defects seen in congenital partial lipodystrophy,
which are due to mutations in the lamin A/C gene.300-302
There is also evidence of increased apoptosis in adipose
tissue from HIV lipodystrophy patients.303 Interestingly,
patients with congenital lypodystrophy or patients with
AIDS and lipoatrophy induced by antiretroviral therapy
have shown dramatic improvement of their ectopic fat
storage syndrome with leptin replacement therapy.304,305
Adiponectin
Adiponectin (also known as AdipoQ, Acrp30, APM1, and
GBP28) is exclusively expressed in adipose tissue306 and
circulates in human serum at very high concentrations of
5 to 30 nM.307 Adiponectin, a 30-kD protein consisting
of an N-terminal collagenous domain and a C-terminal
globular domain, was discovered almost simultaneously
by four separate groups using different methods.306,308-310
Adiponectin exists in the blood in monomer, trimer, hex-
amer, and very high molecular weight forms.311 This
protein is closely related to complement factor Cq1,308
but the folded crystal structure and gene organization
show close similarity to TNF-α.312,313 Arguably, the
most interesting observation is that unlike other adipo-
cytokines whose expression increases with increasing fat
mass, adiponectin is inversely related to fat mass.314-316
How the increased mass of the tissue from which the gene
is expressed reduces expression and/or secretion of the
protein is still an unanswered question. Consistent with
the observation that lipodystrophic patients have very
low concentrations of adiponectin317 and increased ecto-
pic fat, a reduction in circulating adiponectin (as well as
leptin) may facilitate the ectopic storage of fat.
Adiponectin is clearly an insulin-sensitizing hormone,
and administration of recombinant adiponectin in rodents
increases glucose uptake and fat oxidation in muscle,
reduces fatty acid uptake and hepatic glucose production
in liver, and improves whole-body insulin resistance. Two
receptors for adiponectin have been discovered, with the
first isoform (AdipoR1) mostly expressed in skeletal mus-
cle and the second (AdipoR2) mostly in liver.318 Unlike in
mice, gene expression profiling in humans indicates that
both isoforms are highly expressed in skeletal muscle.319
Interestingly, in individuals with normal glucose toler-
ance, muscle expression levels of AdipoR1 and AdipoR2
were lower in subjects with a family history of type 2
diabetes when compared to those without a family his-
tory, and the expression level of both receptors correlated
positively with insulin sensitivity.319 These data indicate
that both isoforms of the receptor may play a role in the
insulin-sensitizing effect of adiponectin probably via a
stimulation of mitochondrial biogenesis, mitochondrial
function, and fat oxidation.320
Even if the signaling cascade for adiponectin is unclear,
there is growing evidence that adiponectin may activate
AMPK, the putative master metabolic regulator described
earlier. Thus, excitement surrounds the potential for
adiponectin (or mimetics of adiponectin) to represent
pharmacologic agents for patients suffering from insulin
resistance and type 2 diabetes. As for leptin, many func-
tions have already been attributed to adiponectin; it has
been linked to cardiovascular disease and endothelial
and immune dysfunctions.321 However, we will focus
mostly on the role of adiponectin as an insulin-sensitizing
hormone.
Adiponectin acts peripherally to improve insulin sen-
sitivity in rodents,322-325 although the proposed mecha-
nisms differ. Combs and colleagues found that increasing
circulating adiponectin concentrations in mice during a
euglycemic clamp increased the rate of glucose infusion by
73%.326 The rates of glucose uptake, glycolysis, and gly-
cogen synthesis were unchanged, but the rate of glucose
production was suppressed by 65%. Chronic infusion
of a proteolytic product of adiponectin prevents weight
gain in mice fed a high-fat diet, whereas mice infused with
 36 ROLE OF THE ADIPOCYTE IN METABOLISM AND ENDOCRINE FUNCTION
full-length adiponectin or saline gained weight.322 The
prevention of weight gain was associated with increased
fat oxidation. The same investigators went on to show
that adiponectin induces fatty acid oxidation in muscle
in vitro and reduces FFA flux following a high-fat meal
or intralipid infusion in vivo.322 Similarly, Yamauchi and
co-workers observed that adiponectin treatment dur-
ing high-fat feeding prevents adipose tissue deposition
in wild-type mice by increasing energy expenditure and
decreasing ectopic fat deposition.323 To determine the
cellular mechanisms underlying this observation, they
measured the expression of genes involved in fatty acid
transport, oxidation, and energy dissipation in both mus-
cle and liver. Adiponectin treatment increased the mRNA
of genes involved in fatty acid uptake and β-oxidation
(specifically, CD36, acyl-CoA oxidase, and uncoupling
protein 2) in muscle and decreased the expression of
genes involved in fatty acid transport in the liver, result-
ing in decreased storage of triglycerides in non-adipose
tissues and indirectly improving insulin sensitivity. Taken
together, the results support the theory that adiponectin
is a regulator of insulin sensitivity through the reduction
of ectopic fat deposition.
Like leptin, adiponectin was shown to directly activate
AMPK in muscle, thereby increasing the phosphorylation
of acetyl coenzyme A carboxylase.325 In turn, malonyl
CoA content is reduced, increasing carnitine palmitoyl-
transferase 1 activity and stimulating fat oxidation. In the
liver, AMPK stimulates fatty acid oxidation and ketogen-
esis and inhibits cholesterol synthesis, lipogenesis, and tri-
glyceride synthesis, whereas it modulates insulin secretion
in pancreatic beta cells (reviewed in reference 327).
Human studies in Pima Indians and Japanese indi-
viduals demonstrated an association between low plasma
adiponectin concentrations and obesity or type 2 dia-
betes.314,316 Furthermore, positive correlations between
plasma adiponectin concentrations and insulin sensitiv-
ity have been reported in several studies.315,316,328 More
importantly, low adiponectin concentrations are pre-
dictive of type 2 diabetes incidence rates over a 5-year
follow-up in Pima Indians.329 Other indicators that low
levels of adiponectin may be involved in the development
of insulin resistance are derived from intervention studies
showing that adiponectin is decreased by behaviors lead-
ing to obesity and diabetes323 and increased in situations
of reduced body fat or increased insulin sensitivity.330,331
At present, adiponectin remains a validated target for
the potential treatment of insulin resistance and type 2
diabetes. However, many questions regarding adiponec-
tin remained to be resolved before contemplating the use
of adiponectin (or mimetics) as therapeutic agents. These
include: (1) which circulating form of adiponectin is bio-
logically active; (2) what are the post-translational mech-
anisms that regulate adiponectin concentration/secretion;
(3) what are the exact sites of action of adiponectin in
central and peripheral tissues; and (4) what is the signal-
ing cascade of adiponectin after binding to its receptor?
Kim and associates332 in Scherer’s laboratory made a big
step toward a better understanding of the function of
adiponectin by creating mice lacking leptin while over-
expressing adiponectin. Surprisingly, these mice have
645
normalized glucose and insulin concentrations and dra-
matically improved glucose tolerance as well as positively
affected serum triglyceride levels despite morbid obesity.
The authors propose that adiponectin acts as a peripheral
“starvation” signal promoting the storage of triglycerides
preferentially in adipose tissue, therefore protecting the
animals from ectopic fat depots.332
Resistin
Resistin is a putative adipocyte-derived “insulin resis-
tance” hormone that was identified during an in vitro
screen for genes upregulated during adipocyte differentia-
tion and downregulated by PPAR-γ agonists.333 In mice,
serum resistin and resistin mRNA expression in adipose
tissue are increased by high-fat diet, and decreased after
rosiglitazone treatment.333 Importantly, blocking resistin
(by antibodies) increases glucose uptake in fat cells and
increases insulin sensitivity. In vitro, resistin decreases
glucose uptake in skeletal muscle cells but does not affect
the “classic” insulin-signaling pathways.334 As expected
from these results, intraperitoneal administration of resis-
tin increased blood glucose following a glucose tolerance
test in mice.333 Taken together, these results led to the
hypothesis that resistin promotes insulin resistance. At
about the same time, two other groups independently
identified resistin.335,336 Kim and colleagues335 observed
that resistin inhibited adipocyte differentiation in 3T3-
L1 cells, suggesting that resistin may promote insulin
resistance by increasing storage of triglycerides in muscle
and liver instead of adipose tissue. Resistin-deficient mice
have low blood glucose after a fast, decreased hepatic
glucose production, and less hyperglycemia when obese,
suggesting a key role in the regulation of hepatic glucose
production.337 Ahima and Lazar reviewed the role of adi-
pokines, including resistin, on the control of energy and
carbohydrate metabolism.338
In humans, the role of resistin in regulating insulin
sensitivity is unclear. In one study, serum resistin was
related to fat mass in young, healthy subjects and was
significantly higher in women than in men,339 but it was
not related to BMI, percent body fat, or insulin sensitiv-
ity in other studies.340,341 Resistin mRNA expression was
shown to be higher in morbidly obese subjects as com-
pared with lean control subjects 342 and higher in individu-
als with a promoter mutation and high levels of oxidative
stress.343 However, in that same study, serum resistin was
not different between non-obese, obese, or obese diabetic
groups. Data in humans indicates that resistin is derived
mainly from macrophages.344 Given the emerging interre-
lationship between inflammation and metabolic disease,
hyperresistinemia may be a biomarker and/or a mediator
of metabolic and inflammatory disease in humans.
TNF-α
TNF-α is a cytokine that is produced by macrophages,
monocytes, endothelial cells, neutrophils, smooth muscle
cells, activated lymphocytes, astrocytes, and adipocytes.345
TNF-α has a variety of functions, such as mediating expres-
sion of genes for growth factors, cytokines, transcription
factors, and receptors. TNF-α is synthesized as a 26-kD
transmembrane protein found on the surface or processed
646 PART 5 DIABETES MELLITUS
to release the 17-kD soluble form.346 Some adipocytokines
are secreted and transported into the blood (i.e., leptin,
PAI-1, and IL-6), whereas TNF-α is secreted and probably
acts locally in an autocrine-paracrine fashion.276
Initial reports implicated TNF-α as an adipocyte-
derived cytokine that was able to block adipocyte differ-
entiation347,348 and was upregulated in human obesity/
insulin resistance.349,350 As a pluripotent cytokine, the
mechanisms by which TNF-α might decrease insulin
action and affect adipocyte functioning are numerous.
As one example, TNF-α suppresses adipocyte-specific
genes with NF-κB being an obligatory signaling inter-
mediate55 and decreases the expression of transcription
factors necessary for adipocyte differentiation.347 In an
autocrine-paracrine fashion, TNF-α blocks further energy
accumulation in adipocytes through “deactivation” of the
insulin-signaling pathway (i.e., insulin resistance),55,351
increased lipolysis, and decreased lipid uptake.352 TNF-α
may be a homeostatic mechanism that may prevent fur-
ther fat deposition by regulating LPL activity and leptin
production.353
TNF-α has been termed an adipostat because its adi-
pose tissue expression is, like leptin, more or less propor-
tional to the degree of adiposity. TNF-α has also been
proposed to link obesity with insulin resistance, with ser-
ine phosphorylation of the insulin receptor substrate-1
being a prominent mechanism for TNF-α–induced insu-
lin resistance.354 TNF-α increases 11β HSD1 mRNA and
enzyme activity and therefore local cortisol production in
human adipocytes,355 thus potentially linking TNF-α to
visceral adiposity. The mechanism by which transcription
is upregulated during energy excess is not entirely clear.
Insulin upregulates TNF-α mRNA, and TZDs appear to
downregulate TNF-α,356 whereas environmental toxins
(such as TCCD) upregulate TNF-α.357
Clinically, higher plasma levels of TNF-α are also asso-
ciated with insulin resistance, higher BMI, higher fasting
glucose levels, and higher LDL-cholesterol levels.358 Using
confirmatory factor analysis and structural equation mod-
eling, it was shown that obesity, dyslipidemia, and TNF-α
were the principal explanatory variables for the various
components of the metabolic syndrome.359 TNF-α has
also been implicated in HIV-associated lipodystrophy.360
Apelin
Apelin is a novel bioactive peptide first identified in 1998
as the endogenous ligand of the orphan G protein–cou-
pled receptor (GPR) APJ.361 A 77–amino acid precursor
can be cleaved into a 55–amino acid fragment and then
into shorter, less-characterized forms. The physiologically
active form of apelin is thought to be apelin-36, although
shorter C-terminal sequences also elicit biological activ-
ity.361 It was only 10 years later that a putative role for
apelin in the etiology of obesity was described. Rayalam
and co-workers first described that apelin’s major role was
to promote angiogenesis in adipose tissue.362 At the same
time, Kunduzova and associates proposed that the angio-
genic response to apelin in adipose tissue—­endothelial
cells migration, proliferation, and capillary f­ormation—
was dose-dependent.363 Furthermore, hypoxia upreg-
ulates the expression of apelin in adipocytes, thus
confirming that the apelin/APJ signaling pathway plays
a critical role in the development of the functional vascu-
lar network in adipose tissue.363 The adipokine apelin is
not only upregulated by hypoxia and insulin but also by
the transcriptional co-activator PGC-1α in human white
adipocytes.364 Finally and importantly, the same labora-
tory presented a convincing argument that acute intrave-
nous injection of apelin had a powerful effect on lowering
plasma glucose by enhancing glucose utilization in skel-
etal muscle and adipose tissue.365 Therefore, apelin will
probably soon be considered as an important target for
the treatment of obesity-related insulin resistance.
The Adipocyte as a Target for the Treatment of Obesity
and Type 2 Diabetes
The brain currently serves as the main therapeutic target
for the treatment of obesity. Given the central role of the
adipocyte in the regulation of body weight and energy
metabolism, the adipocyte should not be discarded as
a target. Classic adipocyte biology, emphasizing the
adrenergic signaling systems, provided the rationale for
the development of beta-3 adrenoreceptor agonists as a
means to increase energy expenditure in muscle and pro-
mote lipolysis in adipose tissue. These efforts have been
hampered by the failure of the drug discovery systems to
identify “clean” beta-3–selective agonists.366 Alternate
lipolytic systems such as the activation of the growth
hormone receptor, blockade of the antilipolytic alpha2
adrenergic receptor, or activation of the recently discov-
ered natriuretic peptide signaling pathway may provide
alternate strategies for increasing adipose tissue lipolysis.
Increasing lipolysis and lipid delivery to peripheral tissue
will produce weight loss only in the presence of increased
energy expenditure or fat oxidation in liver and skeletal
muscle or a reduction in energy intake. The concern with
the lipolytic approach is whether the increased lipid sup-
ply to liver and skeletal muscle will produce or exacerbate
ectopic fat and insulin resistance.
Another avenue to impact insulin action might be
to increase lipid storage in adipose tissue by recruit-
ing “new” adipocytes from preadipocytes. At first, this
approach might be counterintuitive since body weight
is likely to increase. The effectiveness of the antidiabetic
TZDs in animals and humans provide a strong rationale
for this approach. In humans and animals, TZDs increase
lipid storage in adipose tissue, decrease FFA prior to an
improvement in insulin action, and reduce hepatic and
skeletal muscle fat. Such data suggest that sequestration
of lipid in newly recruited or existing adipocytes away
from liver and muscle might be an effective therapeu-
tic strategy. Unfortunately, the acceptability by patients
of the weight gain that occurs in this setting makes this
approach less attractive.
Studies suggest that angiogenesis might precede and
drive adipogenesis.367 This is logical that adipose tissue
might need nutrients and oxygen to develop properly.
However, the opposite concept, namely that anti-angio-
genic agents might prevent weight gain or result in weight
loss, has been demonstrated in animals367 and, along with
targeting adipocytes with a lytic peptide,368 holds promise
as a way to modulate adipose tissue mass and function.369
 36 ROLE OF THE ADIPOCYTE IN METABOLISM AND ENDOCRINE FUNCTION
The secretion of potent endocrine hormones from
adipose tissue is another approach to treat insulin resis-
tance or obesity. As an example, antidiabetic TZDs
upregulate the expression of the insulin-sensitizing hor-
mone adiponectin and increase blood concentrations up
to threefold.370 Given that body weight is regulated by
leptin-dependent and leptin-independent signals, and adi-
pose tissue communicates with the brain to regulate food
intake, additional therapeutic targets and therapeutic
opportunities are likely.
Exogenous cortisol administration or overproduction
of cortisol in conditions such as Cushing’s disease increase
the accumulation of lipid in visceral depots.371,372 The
local production of cortisol within adipose tissue by con-
version of cortisone to bioactive cortisol by the enzyme
11 beta HSD-1 also increases the accumulation of lipid
in visceral depots.373-375 Acting through both adipogenic
and lipogenic pathways, blockade of the local production
of cortisol is likely to reduce visceral adipose tissue mass,
and therapeutic agents are currently in clinical studies.
Beta-3 receptor agonists not only increase energy
expenditure in rodents but also increase the number of
brown adipocytes.376-377 It has been suggested that this
occurs as a result of trans-differentiation of lipid-storing
white adipocytes into energy-consuming brown adipo-
cytes. The hallmark of brown adipocytes is the expres-
sion of the thermogenic uncoupling protein UCP-1. In
rodents, the conversion of WAT into BAT is under genetic
control, and the resulting weight loss improves the fea-
tures of metabolic syndrome. Overexpression of the
transcriptional factor enhancer PGC-1 in human adipo-
cytes in vitro also increases UCP-1 mRNA and protein
and serves as an example of how this might also occur
in humans in vivo.178 Increased energy expenditure and
fat oxidation would result in a decrease in body weight,
although the potential mechanisms remain elusive.378,379
The findings of discrete brown fat depots uncovered by
PET technologies187 should stimulate a renewed effort to
find strategies to induce more brown adipocytes. As noted
earlier, peptide hormones such as natriuretic peptides,
orexin, meteorin, irisin, and FGF-21 are attractive targets.
Lastly, as discussed earlier, once precursor cells are
recruited to differentiate into white adipocytes, they are
647
conceptually permanent. Studies in vivo in humans suggest
that adipocytes are constantly being formed and undergo
apoptosis.119,128 These high turnover rates for adipose
tissue suggest that a reduction in adipocyte recruitment
and/or an increase in adipocyte apoptosis might lead to
a reduction in adipocyte mass. As noted for the lipolytic
pathways, if the excess energy is not completely oxidized,
then a possible outcome might be accumulation of lipid in
skeletal muscle and liver as occurs in lipodystrophy syn-
dromes. This approach would make sense in the setting
of weight loss achieved by other means as a way to reduce
the number of lipid-storing small adipocytes.
Another approach to reverse excess lipid supply to
the liver and skeletal muscle is to modulate lipolysis.
Lipolysis is disordered in obesity and type 2 diabetes
where insulin fails to fully suppress lipolysis. Decreased
lipolysis associated with the decrease in FFA that occurs
with daytime meals might improve insulin action.
Indeed, reducing lipolysis for only 7 days improved
insulin action in vivo.104,180 Preserving the increase in
lipolysis during sleep and exercise might be necessary
to normalize the meal-related and circadian pattern of
lipolysis.
In addition to exercise, which improves blood flow and
insulin sensitivity in adipose tissue, it might be possible
to pharmacologically manipulate lipolysis. Nicotinic acid
therapy is a well-established treatment for hypertriglyc-
eridemia and low HDL cholesterol, and the discovery of
a nicotinic acid receptor (HM74) opens the door for the
development of small-molecule inhibitors of lipolysis.380
Other previously “orphan” GPRs such as the antilipolytic
GPR43 are ripe as targets to improve insulin sensitivity
via suppression of lipolysis.381 GPR43 belongs to a sub-
family of GPRs that include GPR40 and GPR41 and are
all fatty acid receptors. Given the modulation of lipolysis
across the day, the rational design of these drugs should
consider dosing and PK in an attempt to mimic the nor-
mal variation in FFA.
  
• F
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