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Department of Nutrition, University of Tennessee, Knoxville, TN 37996-1900
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT Adipocyte functionObesity genesSummaryREFERENCES |
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KEY WORDS: • leptin • agouti • angiotensin II • eicosanoids • endocrine • adipocyte differentiation.
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Adipocyte function |
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TOPABSTRACTAdipocyte functionObesity genesSummaryREFERENCES |
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(PPAR)3and CCAAT/enhancer binding protein-
(C/EBP) lead to programmed
adipose cell differentiation (Brun et al. 1996
).
Adipose tissue has long been considered to be a passive, inactive
tissue. However, research in the past decade has demonstrated that
adipose tissue plays an important role in energy regulation via
endocrine, paracrine and autocrine signals (Mohamed-Ali et al. 1998
). These functions enable adipocytes to influence metabolic
activity of adipose tissue as well as other tissues, including the
brain, liver and muscle. Several hormones and other factors are
secreted from adipocytes (Table 1
). Most of these factors secreted from adipose tissue act in an
autocrine/paracrine manner to regulate adipocyte metabolism; upon
secretion into the bloodstream, they act as endocrine signals at
multiple distant sites to regulate energy homeostasis (Flier and Maratos-Flier 1998
, Mohamed-Ali et al. 1998
). Thus, adipose cells play a more dynamic role than
previously recognized in physiologic mechanisms, including the
autoregulation of adipocyte growth and development as well as
regulation of whole-body homeostasis. The role of some of these
adipocyte-secreted factors (leptin, agouti, angiotensin II and
eicosanoids) will be discussed.
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Obesity genes |
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TOPABSTRACTAdipocyte functionObesity genesSummaryREFERENCES |
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Leptin, leptin receptors and mechanism of action.
The positional cloning of the ob gene by Friedman’s group
in 1994 led to the discovery of its gene protein product, which was
named leptin (Zhang et al. 1994
). Circulating leptin is
transported to the cerebrospinal fluid where it is available to bind
and activate specific receptors on the hypothalamus that mediate
regulation of energy balance (Tartaglia 1997
).
Consistent with leptin’s cytokine-like structure (Zhang et al. 1997
), the receptor for leptin protein is a single
membrane-spanning protein with structural and functional homology
to the class I cytokine receptor family (Tartaglia 1997
).
Spontaneous mutations in the leptin receptor gene in
db/db mice and fa/fa rats producing defective
leptin receptors lead to severe obesity, with resistance to endogenous
and exogenous leptin (Chen et al. 1996
, Iida et al. 1996
). As a member of the cytokine receptor family, leptin
receptors (Ob-R) lack intrinsic tyrosine kinase
activity, are activated by ligand-induced receptor homo- or
heterodimerization and utilize janus kinases (JAK) and
signal transducers and activators of transcription (STAT) family
proteins (Vaisse et al. 1996
). Multiple splice variants
of Ob-R mRNAs encoding proteins with
identical extracellular domains but different length intracellular
domains have been detected (Tartaglia 1997
).
Ob-Rb encodes a long form of the leptin receptor
found at high levels in the arcuate nucleus within the hypothalamus, a
region that is important for body weight regulation. Low amounts of
Ob-Rb were detected in peripheral tissues
including adipose tissue (Fei et al. 1997
). This long
isoform of the receptor is proposed to mediate leptin’s effects on
body weight homeostasis by decreasing food intake and increasing energy
expenditure (Campfield et al. 1995
). Recent studies have
demonstrated a leptin-inducible inhibitor of leptin signal
transduction. The suppressor of cytokine signaling (SOCS-3) family
blocks leptin-induced activation of STAT3 in cells expressing the
long form of the leptin receptor (Bjorbaek et al. 1999
).
Because SOCS-3 is overexpressed in obesity models, it was suggested as
a potential mediator for leptin resistance related to obesity.
Leptin gene expression and secretion are nutritionally and hormonally
regulated; they are decreased by fasting and cathecolamines and
increased by overfeeding, high fat diets, insulin and glucocorticoids
(Ahren et al. 1997
, Ricci and Fried 1999
,
Russell et al. 1998
). Plasma leptin level and
ob gene expression vary in proportion to the degree of
adiposity in lean and obese animals and humans, indicating a leptin
role as an "adipostat" signal (Considine et al. 1996
).
Role of leptin in energy balance.
Several studies have demonstrated that the hypothalamus is the primary
site for the action of leptin on body weight regulation [reviewed in
Flier and Maratos-Flier (1998)
]. Both peripheral
and central administrations of leptin decrease food intake and body
weight (Campfield et al. 1995
, Halaas et al. 1997
). The effects of leptin on body weight are mediated at
least in part by neuropeptide Y (NPY), a potent stimulator of food
intake (Wang et al. 1997
). However, studies in NPY
knockout mice have shown that the obesity phenotype in NPY-null
ob/ob mice is alleviated only partially, implying that
additional neuropeptides may be involved in the development of
ob/ob phenotype (Erickson et al. 1996
). In
addition to NPY, leptin modulates the levels of several other
neuropeptides that control food intake, including
corticotrophin-releasing hormone, galanin melanin-concentrating
hormone and pro-opiomelanocortins (Flier and Maratos-Flier 1998
).
The majority of obese individuals exhibit elevated circulating leptin
levels and appear to be leptin resistant similar to the syndrome of
db/db obese mice; both mutations in the ob and
ob-R genes have been described in humans but are extremely
rare (Considine et al. 1996
). These mutations are
associated with hyperphagia, excessive weight gain in early life and
severe obesity and hypogonadism (Strosberg and Issad 1999
). Recent cohort studies have shown that daily subcutaneous
recombinant leptin injection in both lean and obese subjects reduced
body weight and fat mass in a dose-responsive manner, a reduction
that also occurred in some obese subjects with elevated serum leptin
concentration (Heymsfield et al. 1999
). Furthermore,
injection of recombinant leptin induced a sustained reduction in
weight, predominantly as a result of a loss of fat in a child with
congenital leptin deficiency (Farooqi et al. 1999
). In
addition to these central effects of leptin on food intake, leptin also
targets peripheral tissues, i.e., overexpression of leptin in
adipocytes decreases fatty acid synthesis (Bai et al. 1996
), suggesting a paracrine effect of leptin on adipocytes.
Leptin also significantly decreases insulin secretion from panceatic
ß cells (Fehmann et al. 1997
). Consequently, leptin,
as well as its agonists and antagonists, is emerging as a novel
therapeutic target in effective drug development and strategies to
treat obesity.
Agouti gene.
Agouti and melanocortins: regulation of coat color and obesity.
Agouti was the first obesity gene to be cloned (Bultman et al. 1992
). Agouti is a paracrine factor expressed in the hair
follicle and is involved primarily in coat color regulation
(Moustaid-Moussa and Claycombe 1999
, Yen et al. 1994
). However, this protein is also expressed and secreted by
human adipose tissue (Kwon et al. 1994
, Wilson et al. 1995
), suggesting a possible role for agouti in modulating
adiposity via paracrine actions on fat cells. The agouti gene encodes a
131–amino acid paracrine factor (Bultman et al. 1992
);
its product normally regulates hair pigmentation patterns by
antagonizing binding of -melanocyte stimulating hormone (-MSH) to
the melanocortin receptor type 1, MC1-R (Lu et al. 1994
). This regulated expression of the agouti gene is
disrupted in mice carrying dominant mutations at this locus, resulting
in the normal agouti protein being produced at high levels in all
tissues of the body (Bultman et al. 1992
,
Moustaid-Moussa and Claycombe 1999
). Ectopic expression
of agouti in Ay and Avy
mutants causes a syndrome of obesity associated with yellow coat color,
increased linear growth, hyperinsulinemia and type II diabetes
[reviewed in Moustaid-Moussa and Claycombe (1999)
].
Utilization of transgenic models successfully demonstrated that
ubiquitous expression of the normal agouti gene is responsible for the
obese phenotype when the wild-type agouti cDNA is placed under the
transcriptional regulation of the ubiquitous promoter ß-actin, BAP
(Klebig et al. 1995
).
The functional agouti protein contains a consensus signal peptide at
the amino terminus, followed by a highly basic region in the middle and
a cysteine-rich carboxyl terminus (Perry et al. 1996
). The carboxyl domain is as biologically active in vitro
as the full-length protein (Willard et al. 1995
).
Mutations in the carboxyl terminus completely eliminated the potential
for both yellow pigmentation and obesity, and decreased agouti
inhibition of -MSH binding to the melanocortin receptor and obesity
(Perry et al. 1996
).
Agouti-related protein (AGRP), a 132–amino acid protein that is 25%
identical to agouti, is normally expressed in the hypothalamus and in
adrenal glands (Ollemann et al. 1997
).
Role of agouti and AGRP in energy balance.
The hypothalamus plays a fundamental role in the control of food
intake; two of the melanocortin receptors, MC3-R and MC4-R, are highly
expressed in this region of the brain (Fan et al. 1997
).
Agouti and AGRP act as potent antagonists to hypothalamic MC4-R, a
receptor involved in regulation of food intake, and AGRP is believed to
be the natural ligand for MC4-R (Fan et al. 1997
,
Lu et al. 1994
, Ollemann et al. 1997
).
Similar to the effects of agouti ectopic overexpression in mice,
ubiquitous expression of AGRP causes obesity, but without altering
pigmentation (Ollemann et al. 1997
). The severity of the
obesity syndrome in AGRP transgenic mice resembles that of the
melanocortin receptor 4 (MC4-R) knockout mice (Huszar et al. 1997
).
The human homologue of the agouti gene, referred to as agouti signaling
protein (ASIP) is 85% identical to the mouse gene (Kwon et al. 1994
, Wilson et al. 1995
). Unlike mouse agouti,
human agouti is expressed in adipose tissue (Kwon et al. 1994
), indicating a possible role of agouti in regulation of
adipocyte metabolism.
Obese yellow mice exhibit elevated levels of plasma leptin
(Halaas et al. 1997
). Similarly, BAP-agouti
transgenic mice, which ubiquitously express agouti, recapitulate the
yellow mouse obesity syndrome (Klebig et al. 1995
) and
express very high levels of plasma leptin (Claycombe et al. 2000
, Zemel et al. 1998
). This increase in
plasma leptin is paralleled by a significant increase in adiposity in
these models (Halaas et al. 1997
, Zemel et al. 1998
). By contrast, transgenic mice expressing agouti
specifically in adipose tissue under the control of the aP2 promoter
(aP-agouti transgenic line) do not become obese; however, daily insulin
injections to these mice significantly increased their body weight
(Mynatt et al. 1997
), suggesting an insulin-agouti
interaction to promote weight gain in vivo. aP2-agouti mice are also
hyperleptinemic compared with their control littermates
(Claycombe et al. 2000
), and in vitro studies confirmed
that this hyperleptinemia is due at least in part to direct
upregulation of adipocyte leptin by agouti (Claycombe et al. 2000
).
In addition to hyperleptinemia, obese yellow mice exhibit
increased lipogenesis and depressed lipolysis (Jones et al. 1996
, Moustaid-Moussa and Claycombe 1999
,
Yen et al. 1994
). In agreement with these
characteristics, agouti treatment of cultured adipocytes stimulates
fatty acid and triglyceride synthesis (Jones et al. 1996
). In addition, agouti inhibits both basal and
agonist-stimulated lipolysis in cultured human adipocytes
(Xue et al. 1998
). Agouti-mediated lipogenesis and
antilipolysis were both prevented in vivo and in vitro by calcium
channel blockade, demonstrating that agouti’s effects on adipocytes
are mediated at least in part by intracellular calcium (Jones et al. 1996
, Kim et al. 1996
, Xue et al. 1998
). Agouti is also expressed in the pancreas where it
increases insulin secretion via a calcium-dependent mechanism
(Xue et al. 1999
). Thus, agouti’s central effects on
food intake, combined with adipocyte expression of agouti and
hyperinsulinemia, may contribute to obesity.
Angiotensin II.
Expression of the renin angiotensin system (RAS) in adipose tissue.
Angiotensin II is a well-known hypertensive hormone, generated in
the renin angiotensin system, RAS (Campbell 1987
).
Components of the RAS include angiotensinogen (AGT), the only known
precursor for angiotensin II (AII), which is cleaved by the kidney
renin and the lung angiotensin-converting enzyme, ACE, into
angiotensin II (Campbell 1987
). Angiotensin II acts on
target cells by binding to its G-protein–linked seven transmembrane
receptors, primarily AT1 and
AT2. The RAS components are expressed locally in
other tissues, including adipose tissue (Jones et al. 1997a
, Saye et al. 1989
, Schling et al. 1999
). Both AII receptor subtypes, AT1
and AT2, are expressed in adipose cells
(Crandall et al. 1994
, Darimont et al. 1994
, Jones et al. 1997b
). Collectively, these
findings demonstrate that adipose tissue is an important peripheral
site for the generation of AII, suggesting significant function of
adipocyte-derived AII in adipose tissue development and metabolism
and possibly obesity-linked hypertension.
Angiotensin II, obesity and adipocyte metabolism.
Epidemiologic studies have shown a tight correlation between
accumulation of intra-abdominal fat and hypertension (Cooper et al. 1997
). A significant correlation between plasma AGT
level, blood pressure and the ob gene product leptin, which
is proposed as an endogenous marker of adiposity, has been reported
(Schorr et al. 1998
). However, the contribution of
adipose-derived AII to pathophysiologic hypertension is not well
understood. Alterations of AII production and function in obese rats
appear to decrease energy expenditure associated with brown adipose
tissue (BAT) thermogenesis, possibly contributing to development of
obesity (Cassis 1994
).
In light of a potential physiologic role for AII in regulating
adiposity, AGT expression is differentiation dependent (Saye et al. 1989
). A positive relationship exists between expression of
AGT mRNA and protein, and relative rates of adipocyte growth in rats
(Harp and DiGirolamo 1995
). Further, under conditions of
genetic obesity, AGT synthesis by adipocytes is altered
(Frederich et al. 1992
, Jones et al. 1997b
) compared with that of lean littermates, suggesting a
potential link between obesity and functional local RAS in adipose
tissue. AGT expression is nutritionally and hormonally regulated in
adipocytes; it is reduced by fasting, enhanced by overfeeding
(Frederich et al. 1992
) and increased by high fat diets
and fatty acids concomitant with enlargement of fat mass
(Safonova et al. 1997
, Zorad et al. 1995
). In addition, although ß-adrenergic receptor agonists
decrease AGT expression in 3T3-L1 adipose cells (Jones et al. 1997b
), glucocorticoids upregulate AGT gene expression in
Ob1771 (Aubert et al. 1997
). However, inconsistent
regulation of AGT by insulin was reported (Aubert et al. 1998
, Jones et al. 1997b
).
AII exerts its action via at least two distinct receptors subclassified
as AT1 and AT2. Studies by
Crandall et al. (1994)
demonstrated that the
AT1 receptor mediates an age-dependent
increase in rat adipocyte size. AII also promotes adipocyte
differentiation by stimulating release of prostacyclin
(PGI2) from mature fat cells; this has an
autocrine adipogenic effect in vitro through an
AT2-receptor–mediated mechanism (Darimont et al. 1994
). In agreement with these findings, AII enhances
expressions of prostaglandin endoperoxide synthase (PGHS-1) and PGHS-2
mRNA in mature adipocytes, thus promoting prostaglandin (PG) production
(Borglum et al. 1997
). Consistent with the adipogenic
effects of AII, we have shown that this hormone upregulates lipogenesis
and increases triglyceride storage via an
AT2-dependent mechanism, concurrent with elevated
transcription rate of ob gene in 3T3-L1 and human adipose
cells (Jones et al. 1997a
). Collectively, these findings
suggest that adipocyte-derived AII upregulates secretion of leptin
and adipocyte markers, in part via a PG-mediated mechanism.
Eicosanoids.
Arachidonate metabolism.
The formation of arachidonate [20:4(n-6)] is a process involving the
elongation and desaturation of dietary linoleic acid [18:2(n-6)] or
direct consumption of arachidonate. Arachidonate is found in cells in
relatively abundant amounts but incorporated almost exclusively at the
sn-2 position of membrane phospholipid (Wahle 1990
). Arachidonate is released from phospholipids by the
action of hormone-regulated phospholipases and processed by
cyclooxygenases (COX), lipoxygenases or cytochrome p450 oxygenases to
the various physiologically important eicosanoids (Piomelli 1993
).
Role of arachidonate metabolites in adipogenesis.
Several studies have demonstrated that arachidonate metabolites
modulate positively or negatively differentiation and maturation of
adipose tissue (Shillabeer et al. 1998
). Prostaglandin
E2 (PGE2) and prostacyclin
(PGI2) are the two major PG produced from rodent
and human adipocytes (Hyman et al. 1982
,
Richelsen 1992
). PGE2 negatively
modulates cAMP production and thus lipolysis in rat and human
adipocytes via interaction with its specific receptors, suggesting
that this antilipolytic effect of PGE2 may
contribute to hypertrophic development of adipose tissue
(Vassaux et al. 1992
). Conversely,
PGI2 and carbaprostacyclin
(cPGI2), its stable analog, are proposed as
adipogenic-hyperplastic effectors in Ob1771 cell line
(Darimont et al. 1994
). These eicosanoids have been
reported to activate the three known mammalian peroxosome
proliferator–activated receptors (PPAR, 
and ), indicating
that cPGI2 promotes differentiation via PPAR
(Hertz et al. 1996
). Another PG,
15-deoxy-
12,14-prostaglandin
J2 (PGJ2) is an important
ligand for PPAR, an adipogenic transcription factor (Forman et al. 1995
). In contrast, PGF2
inhibits the differentiation of 3T3-L1 and rat preadipocytes
(Miller et al. 1996
, Vassaux et al. 1994
). Studies of Lehmann et al. (1997)
have
addressed the mechanism of stimulation of differentiation by
indomethacin, an inhibitor of PG synthesis. At low concentrations,
indomethacin exhibits its inhibitory effects on COX, but at high
concentrations, it directly binds and activates PPAR and and
thus induces the adipocyte differentiation. These studies indicate that
PPAR plays an important role in mediating indomethacin-induced
adipogenesis. Indomethacin exerts inhibitory effects on leptin
secretion at the concentration at which it activates PPAR in
differentiating adipocytes, implying that indomethacin-induced
PPAR activation may be involved in initial-stage rather than the
later-stage of differentiation (Sinha et al. 1999
).
In summary, arachidonate metabolites produced locally by adipocytes
participate in adipocyte growth and development via interactions not
only with their cell surface receptors but also nuclear receptors and
thus may act as important paracrine/autocrine effectors in
adipogenesis.
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Summary |
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TOPABSTRACTAdipocyte functionObesity genesSummaryREFERENCES |
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FOOTNOTES |
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3 Abbreviations used: AII, angiotensin II; ACE,
angiotensin-converting enzyme; AGRP, agouti-related protein;
AGT, angiotensinogen; -MSH, -melanocyte stimulating hormone;
ASIP, agouti signaling protein; BAP, ß-actin promoter; BAT, brown
adipose tissue; C/EBP, CCAAT/enhancer binding protein-; COX,
cyclooxygenase; cPGI2, carbaprostacyclin; JAK,
janus kinases; MC1-R, melanocortin receptor type 1; NPY,
neuropeptide Y; Ob-R, leptin receptor;
PG, prostaglandin; PGHS-1, prostaglandin endoperoxide synthase;
PGI2, prostacyclin; PPAR, peroxisome
proliferator–activated receptor-; RAS, renin angiotensin system;
SOCS-3, suppressor of cytokine signaling; STAT, signal transducers and
activators of transcription.
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REFERENCES |
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TOPABSTRACTAdipocyte functionObesity genesSummaryREFERENCES |
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