Review

This Review is part of a thematic series on Adipocyte Signaling in the Cardiovascular System, which includes the
following articles:
Adipose Tissue, Inflammation and Cardiovascular Disease

Adipocyte Signaling and Lipid Homeostasis: Sequelae of Insulin Resistant Adipose Tissue

Diabetic Cardiomyopathy: The Search for a Unifying Hypothesis

Adipocyte Signaling and the Vasculature
PPARgamma Activation and Effects on the Vasculature Phillip Scherer, Guest Editor

Adipocyte Signaling and Lipid Homeostasis

Sequelae of Insulin-Resistant Adipose Tissue
Yi-Hao Yu, Henry N. Ginsberg

Abstract—For many years adipose tissue was viewed as the site where excess energy was stored, in the form of
triglycerides (TGs), and where that energy, when needed elsewhere in the body, was released in the form of fatty acids
(FAs). Recently, it has become clear that when the regulation of the storage and release of energy by adipose tissue is
impaired, plasma FA levels become elevated and excessive metabolism of FA, including storage of TGs, occurs in
nonadipose tissues. Most recently, work by several laboratories has made it clear that in addition to FA, adipose tissue
communicates with the rest of the body by synthesizing and releasing a host of secreted molecules, collectively
designated as adipokines. Several recent reviews have described how these molecules, along with FA, significantly
effect total body glucose metabolism and insulin sensitivity. Relatively little attention has been paid to the effects of
adipokines on lipid metabolism. In this review, we will describe, in detail, the effects of molecules secreted by adipose
tissue, including FA, leptin, adiponectin, resistin, TNF-␣, IL-6, and apolipoproteins, on lipid homeostasis in several
nonadipose tissues, including liver, skeletal muscle, and pancreatic ␤ cells. (Circ Res. 2005;96:1042-1052.)
Key Words: lipids 䡲 fatty acids 䡲 adipose tissue 䡲 insulin resistance 䡲 cytokines

F or many years adipose tissue was viewed as playing a

passive role in total body lipid and energy homeostasis.
Adipose tissue was the site where excess energy was stored,
in the form of triglycerides (TGs), and where that energy,
when needed elsewhere in the body, was released in the form
of fatty acid (FA). Work by numerous laboratories during the
second half of the 20th century made it clear that under
normal conditions, the storage and release of TG and FA,
respectively, are both coordinated and tightly regulated so
that lipid fuels are stored during the immediate postprandial
periods and released during periods of fasting. The biochem-
istry of key molecules critical to coordinating storage and
release of energy, such as lipoprotein lipase (LPL) and
hormone sensitive lipase (HSL), was characterized in detail
during that period. More recently, it has become clear that
when the regulation of storage and release of energy by
adipose tissue is impaired, particularly when release of FA
becomes dissociated from energy requirements in other or-
gans and tissues, plasma FA levels become elevated and
excessive metabolism of FA, including storage of TG, occurs
in nonadipose tissues.
Our initial understanding of how fat tissue communicates
with other tissues and organs to integrate total body lipid
homeostasis was limited to the effects of circulating FA on
hepatic lipid and glucose metabolism. During the last 15
years, however, it has become clear that adipose tissue–

Original received January 13, 2005; revision received March 30, 2005; accepted April 1, 2005.
From the Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY.
Correspondence to Henry N. Ginsberg, MD, Department of Medicine, PH 10 –305, Columbia University College of Physicians and Surgeons, 630 West
168th St, New York, NY 10032. E-mail hng1@columbia.edu
© 2005 American Heart Association, Inc.
Circulation Research is available at http://www.circresaha.org DOI: 10.1161/01.RES.0000165803.47776.38

1042
 Yu et al
derived FA can affect lipid metabolism in several tissues,
including muscle and pancreatic ␤ cells. The expanded view
of ectopic metabolism or accumulation of FA or TG is that it
causes dysfunction, or lipotoxicity, in these organs and
tissues. Most recently, work by several laboratories has
further expanded our view of the way adipose tissue commu-
nicates with, and affects, total body energy homeostasis. We
now know that in addition to FA, adipose tissue communi-
cates with the rest of the body by synthesizing and releasing
a host of secreted molecules, collectively designated as
adipokines. These molecules, along with FA, have significant
effects on total body glucose and lipid metabolism, and
insulin sensitivity. Several recent articles have described the
effects of the adipokines on glucose metabolism, insulin
sensitivity, and inflammation;1–5 little has been written about
their effects on lipid metabolism. In this review, we will
combine a detailed description of the effects of FA on total
body lipid metabolism with an update on the rapidly evolving
understanding of the role of adipokines in lipid homeostasis.
Normal Adipose Tissue Regulates Partitioning
and Utilization of Lipids by the Body
After a meal, dietary TG is digested by pancreatic lipase in
the small intestines and absorbed by intestinal enterocytes as
FA and sn-2-monoacylglycerols.6 These lipid molecules re-
assemble as TG and are then exported into the circulation as
chylomicrons. In the fed state, adipose tissue is the major site
for uptake of dietary TG FA, after LPL-mediated hydrolysis
of chylomicron TG. LPL is produced mainly in adipose tissue
and muscle, secreted by those tissues, and transported to the
surfaces of capillary endothelial cells in these tissues. LPL
binds to proteoglycans at the luminal side of the capillary
blood vessels, where it interacts with TG-rich lipoprotein
particles7,8 and, in the presence apolipoprotein (apo) CII,9
hydrolyzes TG. ApoCIII inhibits LPL-mediated TG hydroly-
sis, and the ratio of apoCII to apoCIII may be critical in
regulating the delivery of dietary TG to adipose tissue.10
Insulin is a major regulator of LPL synthesis and activity in
adipose tissue. In the fed state, whereas LPL is downregu-
lated in muscle, it is upregulated in adipose tissue.7,8 The
opposite regulation characterizes the fasted state.
The FAs that are released in high concentrations by
lipolysis of TG-enriched lipoproteins have to be efficiently
trapped in the local adipose tissue to prevent high FA flux
through the plasma to tissues that do not, at that moment,
require FA as an energy source.8 Both inhibition of adipocyte
HSL-mediated TG lipolysis during the hyperinsulinemic
postprandial period and efficient acylation of newly arrived
FA inside adipocytes help create a gradient for FA uptake in
adjacent adipose tissue. Physical channeling of FA through
the endothelial cells to the adipocyte also occurs during
lipolysis.11 Then, FA can be rapidly taken up and trapped,
most likely, by a combination of passive diffusion12 and the
action of fatty acid transport proteins.13
Acylation-stimulating protein (ASP) is an adipocyte-
secreted protein that may also play an important role in the
efficient adipocyte trapping of FA released after lipolysis of
lipoprotein TG.14 ASP is generated by the interaction of
complement C3 with factors B and D (the latter is also called
Adipocyte Signaling and Lipid Homeostasis 1043
adipsin). The result is cleavage of the N-terminal of C3,
producing C3a, which is then cleaved by plasma carboxypep-
tidase to produce C3desarg or ASP. Studies in adipocytes
indicate that ASP increases glucose uptake (a substrate for
glycerol formation) and the activity of diacylglycerol acyl-
transferase (DGAT), thereby facilitating use of FA for TG
synthesis. Additionally, ASP has been shown to increase
reesterification of FA released from TG by HSL, as well as
reduce HSL-mediated lipolysis. In humans, fasting ASP
levels correlate with postprandial TG clearance.15 ASP-
deficient mice have delayed postprandial TG clearance
(males on a mixed C57BL/6x129Sv background)16 and re-
duced body weight and fat mass (females on the same mixed
background),17 even on the ob/ob background.18 Addition-
ally, intraperitoneal injection of ASP facilitated postprandial
TG clearance in several mouse models of obesity and insulin
resistance.16 However, other investigators, using the same
mouse (they had originally generated a complement C3
knockout mouse that would, by definition, also be deficient in
ASP), did not find alterations in energy metabolism or lipid
metabolism.19 This controversy remains unresolved at pres-
ent, although the weight of evidence favors some role for
ASP in postprandial TG and FA partitioning into fat.
As a result of these various processes, 90% to 100% of
LPL-released FA is trapped by adipocytes after feeding.20
The efficiency of TGFA uptake by adipose tissue in normal
humans is evidenced by the fact that postprandial plasma
FFA levels are actually lower than fasting levels.20 This
reduction in plasma FA results both from inhibition of
adipose tissue HSL-mediated TG lipolysis and the facilitated
uptake of chylomicron or very low density lipoprotein (VLD-
L)– generated FA.
By contrast, during the fasting state, insulin levels are low,
HSL is activated, and catecholamine-stimulated adipose tis-
sue lipolysis becomes unopposed. Additionally, adipose tis-
sue LPL activity is downregulated and muscle LPL is
upregulated. Thus, during fasting, FA is released from fat,
plasma FA levels rise, and muscle uptake of FA increases. FA
flux to liver also increases during fasting, contributing energy
for hepatic gluconeogenesis and ketogenesis. During longer
periods of fasting, FA becomes the primary fuel in organs
where glucose is not an obligatory fuel, including skeletal
muscle, heart, and the renal cortex. In this manner, glucose is
spared for its required utilization by the central nervous
system.
Insulin-Resistant Adipose Tissue and
Dysregulation of Lipid Partitioning
and Utilization
Insulin resistance is traditionally assessed by insulin’s ability
to promote normal glucose metabolism. The physiological
role of insulin is, however, much broader, and includes the
metabolism of all 3 macronutrients (carbohydrates, lipids,
and proteins) as well as cellular growth. Insulin’s action on
lipid metabolism is analogous to its role in glucose metabo-
lism, ie, promoting anabolism and inhibiting catabolism.
Specifically, insulin upregulates LPL and stimulates gene
expression of intracellular lipogenic enzymes, such as acetyl-
CoA carboxylase (ACC) and fatty acid synthase (FAS).21 In
1044 Circulation Research May 27, 2005
addition, insulin inhibits adipocyte HSL through inhibition of
its phosphorylation.22
In the insulin-resistant state, the responses of both LPL and
HSL to insulin are blunted. Thus, with insulin resistance,
inefficient trapping of dietary energy occurs both because of
decreased LPL-mediated lipolysis of chylomicron-TG and
ineffective inhibition of HSL-mediated lipolysis in adipose
tissue.23 Postprandial lipemia and elevated plasma FA levels
are well-recognized abnormalities in obesity and insulin
resistance.24 Reduced adipose tissue uptake and storage of TG
FA during the postprandial period results in greater partition-
ing of dietary lipids to nonadipose tissues, including muscle
and liver.25,26 Thus, the metabolic consequence of inadequate
insulin action at the adipocyte during the fed state is a
condition similar to the normal fasting state, when insulin
levels are appropriately low. However, in the fed state, this
maladaptive response creates a situation in which postpran-
dial FA are directed to various nonadipose tissues and organs
at a time when lipid energy is not needed. The specific
consequences of increased FA flux to nonadipose tissues are
discussed in more detail in the following sections.
The ultimate example of the loss of physiological lipid
partitioning is total lipodystrophy, a disorder in which there is
no adipose tissue.27 Several genes have been identified that
can cause total lipodystrophy, including 1-acylglycerol-3-
phosphate O-acyltransferase 2 (AGPAT2), which converts
1-acyl glycerol phosphate to 1,2 diacylglycerol phosphate
(phosphaditic acid); without AGPAT2, TG synthesis and
adipogenesis are disrupted.28,29 A second gene, called seipin,
has no known function, and the way in which it causes
lipodystrophy is unknown.29 There are partial lipodystro-
phies, some of which have been associated with mutations in
the gene for lamins A and C (LMNA), and in the PPAR␥
gene.30 In total lipodystrophy, plasma FA levels are very
high, and TG accumulates in muscle, liver, islet cells, and
plasma, resulting in insulin resistance, hypertriglyceridemia,
and defective insulin secretion with diabetes.31 It is note-
worthy that patients with total lipodystrophy have no intra-
abdominal fat, including no visceral fat, and yet have severe
insulin resistance. In partial lipodystrophy, ectopic fat depo-
sition occurs in several organs, and there is also visceral fat,
hypertriglyceridemia, and insulin resistance.
Rodent models of lipodystrophy32–34 have provided impor-
tant insights regarding the effects of a failure to partition FA
to adipose tissue. These models all have ectopic fat, particu-
larly fatty livers, and both insulin resistance and increased
secretion of VLDL TG.
Role of Increased Plasma FA Flux to the Liver
and Increased VLDL Secretion
As noted, insulin resistance in adipose tissue will disrupt
normal lipid partitioning in both the fed and fasting states,
and nonadipose tissues will be faced with increased FA
delivery. Based on blood flow, and a very high capacity to
take up plasma FA, the liver will be a major recipient of those
FA. It is likely that both “flip-flop” diffusion processes12 and
one or more fatty acid “receptors” or “transport proteins”13
are involved in the high capacity of the liver to take up FA.
In addition, intracellular proteins that bind or chemically
modify FA, such as long-chain acyl-CoA synthetase
(ACLS),35,36 are very likely to facilitate the net transport of
FA from the plasma into hepatocytes.
Increased plasma FA flux to the liver as a cause of
increased VLDL apoB and TG secretion has been observed
both in vitro and in vivo.37–39 Studies of cultured liver cells
have often, but not always, shown FA to stimulate apoB
secretion.39 Some of the inconsistencies seem to derive from
the fact that when studying primary rodent hepatocytes, the
composition and caloric content of the prior diet may be
important determinants of the response to FA; fast rats, or rats
fed high carbohydrate diets, respond to increased FA with a
rise in VLDL assembly and secretion. Several in vivo rodent
models also support a close link between increased plasma
FA flux to the liver and increased apoB secretion. In the
sucrose-fed hamster,40 which is a model of insulin resistance
and hypertriglyceridemia, increased plasma FA levels are
correlated with increased assembly and secretion of apoB-
lipoproteins (LPs). Studies with mice having genetic alter-
ations in the fatty acid transporter, CD36 (also called FA
translocase or FAT), indicate that plasma FA flux to the liver
is a critical stimulus for VLDL secretion. Thus, when CD36
was deleted in all tissues (CD expression is normally low in
the liver), plasma FA and TG levels were increased despite an
apparent increase in overall insulin sensitivity.41 By contrast,
in mice overexpressing CD36 in muscle, lower levels of
plasma FA and TG were observed despite concomitant
overall insulin resistance. Importantly, mice lacking HSL had
significantly reduced levels of plasma FA and TG, and also
reduced rates of hepatic TG secretion.42 We recently demon-
strated, in vivo, that intravenous delivery of albumin-bound
FA could stimulate secretion of apoB from livers of normal
mice.43
Increased apoB secretion was first demonstrated in insulin-
resistant and diabetic subjects,44 in whom increased FA flux
was linked to both VLDL TG and apoB secretion.45 Obese
patients were also shown to incorporate plasma FA efficiently
into VLDL TG.46 Increased VLDL apoB and TG secretion
has been documented in a patient with lipodystrophy, severe
insulin resistance, and high levels of plasma FA.47 Impaired
insulin-mediated inhibition of FA release by adipose tissue
has been related to increased VLDL secretion in subjects with
familial combined hyperlipidemia.48 The most direct evi-
dence was provided by studies in which intravenous infusions
of the TG-phospholipid emulsion, intralipid, resulted in both
acute elevations in plasma FA levels and increased secretion
of both apoB and TG in healthy young men.38
FA delivery to the liver could also lead to increased
secretion of VLDL by inhibiting insulin-stimulated apoB
degradation.49 Increased availability of FA, either from en-
dogenous TG stores or as dietary TG, not only causes insulin
resistance in skeletal muscle, but also in the liver50,51; this
would affect insulin’s ability to inhibit VLDL secretion.
Indeed, although hyperinsulinemia has been shown to reduce
apoB secretion in normal humans,52,53 insulin is ineffective in
obese52 or diabetic54 subjects.
Diminished LPL activity could reduce partitioning of
TGFA to adipose tissue from chylomicron TG (in the fed
state) and VLDL TG (in the fasted state). This would leave
 Yu et al
TG-enriched remnant lipoproteins in the circulation, and the
liver would be the major repository for these TGFA. Hepatic
uptake of apoB-lipoprotein remnants occurs by a multioption
process that involves LDL receptors (the primary mediator of
uptake), LDL-receptor–related protein (LRP), hepatic lipase
(HL), possibly LpL associated with remnants, proteoglycans,
and scavenger receptor-B1 (SR-B1).55,56 It is clear from both
in vitro57 and in vivo58 studies that uptake by the liver of
TG-enriched LPs can stimulate subsequent secretion of he-
patic apoB-LPs. It is not clear, however, if LpL/HL-liberated
lipoprotein FA or lysosomal-liberated lipoprotein FA have
similar effects on apoB-LP assembly and secretion. Indeed,
our recent studies43 demonstrate qualitative differences be-
tween FA delivered by albumin and FA derived from the
internalization of remnants on the assembly and secretion of
VLDL.
Despite the ability of the liver to assemble and secrete
VLDL TG, and thereby “unload” excess FA, fatty liver is a
common consequence of inappropriate flux of plasma FA and
lipoprotein remnant TGFA to that organ.59,60 Why the liver is
unable to efficiently unload the excess FA is unclear, but
several possibilities can be considered. First, delivery of
albumin-bound FA may have different quantitative and qual-
itative effects compared with delivery of remnant lipoprotein
TGFA, with the latter less potent at stimulating secretion of
VLDL.43 Second, the state of lipogenesis in the liver may be
important; excessive de novo fatty acid synthesis, driven by
hyperinsulinemia61or hyperglycemia,62 in the face of in-
creased exogenous FA influx, may overwhelm the secretory
capacity of the liver. Third, insulin-mediated degradation of
apoB will clearly be a major determinant of the liver’s ability
to assemble and secrete VLDL. Thus both the degree of
hyperinsulinemia, and the degree of hepatic insulin resis-
tance, will be critical determinants of VLDL secretion and,
therefore, TG accumulation in the liver. For example, if
insulin-mediated degradation of apoB is preserved in the
setting of increased FA flux and hepatic lipogenesis, fatty
liver would be a likely outcome.
Role of Increased FA Flux to Muscle and
Insulin Resistance
Beginning with Randle’s publication of the “glucose-fatty
acid cycle” in skeletal muscle in 1963,63 it has become
increasingly clear that disordered FA metabolism is critical in
the pathophysiology of muscle insulin resistance.50 Although
this is not a review of insulin action or glucose metabolism,
it is important to review the effects of increased FA flux to
muscle on FA metabolism, and therefore, insulin/glucose
metabolism in that tissue. Recent studies have provided
strong evidence that the ability of FA to interfere with insulin
signaling and glucose transport into muscle correlates with
the generation of FA metabolites, such as fatty acyl CoA
molecules or diacylglycerol. Increased generation of these
metabolites as a response to inappropriate increases in FA
uptake can stimulate serine-phosphorylation of IRS-1, and
possibly IRS-2, via the actions of certain protein kinase C
isoforms.64,65 Targeted disruption of PKC-␪ in mice protected
them from FA-induced insulin resistance.66 Recent evidence
also suggests that PKC-mediated serine phosphorylation of
Adipocyte Signaling and Lipid Homeostasis 1045
inhibitor of ␬␤ kinase (IKK␤), leading to its degradation and
the unregulated translocation of nuclear factor-␬␤ (NF-␬␤)
into the nucleus, may also be important to FA-induced insulin
resistance.67 We realize that there are many other potential
reasons for muscle to be insulin resistant, but it is clear that
simply providing excess FA can induce insulin resistance.50
Why are potentially harmful intermediates of FA metabo-
lism accumulating in muscle of insulin-resistant individuals?
Is it just increased FA flux into the muscle, especially when
those FA are not needed for energy, or is there a defect in FA
utilization? Of interest in this regard are the findings that
insulin-resistant and diabetic individuals have decreased frac-
tional and, in some cases, absolute uptake of FA by mus-
cle.68,69 However, the combination of normal or only slightly
reduced plasma FA levels during the immediate postprandial
period in insulin-resistant individuals, a time when plasma
FA levels should be dramatically suppressed,20 together with
modestly reduced extraction of FA by muscle, would still
create a situation where FA supply is out of proportion to the
need for FA to supply energy to that tissue. Additionally,
there is considerable evidence that mitochondrial oxidation of
FA is defective in insulin-resistant individuals,70,71 and that
this can be reversed by weight loss and exercise.72 Excess FA
trapping in muscle, together with reduced FA oxidation,
would result in increased TG synthesis. Indeed, increased
intramyocellular TG is highly correlated with insulin resis-
tance.73 Although some investigators have suggested that
intramyocellular TG is the lipotoxic substance in muscle, it is
more likely only a marker of reduced oxidation of FA relative
to FA availability.74
Role of Increased FA Flux to ␤ Cells and Insulin
Secretory Defects
Plasma FA can be taken up by pancreatic ␤ cells where it can
stimulate insulin secretion.75 The latter appears to occur as
FAs are used to generate long-chain fatty acyl CoA, which
can contribute to the synthesis of signaling molecules such as
DAG and phosphatidic acid (PA) or directly stimulate PKC
isoforms involved in secretion.76 The ability of FA to stim-
ulate insulin secretion requires the presence of stimulatory
glucose; the potential reasons for this interaction include the
generation from glucose of (1) ␣ glycerol phosphate, which is
needed as the backbone molecule for DAG and PA, and (2)
malonyl CoA, which inhibits FA oxidation and stimulates
lipid formation. Of particular relevance to insulin resistance is
the finding that circulating FA are critical for the response of
the pancreas to glucose in the fasting state.77 Thus, the high
basal insulin response characteristic of insulin resistance
might derive, at least in part, from increased levels of FA
before the administration of glucose. High-plasma FA uptake
by ␤ cells will also lead to increased storage of FA as TG.
The release of TGFA from cytosolic TG droplets by HSL and
associated lipases is another source of FA that could stimulate
insulin release. Indeed, HSL-deficient mice have reduced
insulin response to glucose.78
There is also clear evidence, however, that continued
high-cytosolic FA concentrations lead ultimately to decreased
insulin secretion.76 Several mechanisms have been reported,
including inhibition of insulin synthesis,79 inhibition of the ␤
1046 Circulation Research May 27, 2005
cell transcription factor, IDX-1,80 and the combination of
reduced expression of acetylCoA carboxylase and increased
expression of CPT-1.81 In a scheme that parallels the normal
interaction of FA and glucose on insulin secretion, the
deleterious effects of sustained high FA levels in the islet may
require simultaneously elevated levels of glucose.82 Finally,
chronic exposure of ␤ cells to high FA and glucose was
shown to cause apoptosis in ZDF rats.75,83
Role of Adipokines in Lipid Metabolism
Leptin
Leptin is a 16-kDa protein synthesized mainly in adipose
tissue. The leptin gene was identified as the causative
mutation in ob/ob mice.84 Numerous reviews have been
published describing its regulation and its role in eating and
energy homeostasis.85,86 However, studies from a number of
laboratories, using in vitro and in vivo rodent models,
indicate a direct role for leptin in lipid metabolism. The effect
on lipid metabolism may be mediated both through central
and peripheral actions of leptin. For example, central admin-
istration of leptin increased resting metabolic rates, resulting
in reduced TG content in both adipose and nonadipose
tissues, as well as reduced plasma-free FA and TG levels in
pair-fed Sprague-Dawley rats.87 Leptin may also have auto-
crine or paracrine effects on adipocyte fat metabolism:
incubation of mouse adipocytes with leptin stimulates lipol-
ysis of intracellular TG, and this effect was not seen in db/db
mice lacking leptin receptors.88 Overexpression of leptin in
adipocytes also reduced gene expression of acetyl CoA
carboxylase (ACC).89 In other tissues, leptin also appears to
inhibit lipogenesis and stimulate FA oxidation.83 The mech-
anism underlying these actions of leptin may be via binding
to its receptor with succeeding activation of the Jak/Stat
pathway90 or by direct stimulation 5⬘-AMP activated protein
kinase (AMPK),91 which will phosphorylate and thereby
inhibit ACC activity and lipogenesis. Leptin also can inhibit
the expression of sterol response element binding protein-1c
(SREBP-1c) in liver, pancreatic islets, and adipose tissue,
thereby inhibiting lipogenesis in those tissues.
The importance of leptin in regulating lipid metabolism in
several tissues is best exemplified by the lipotoxicity that is
associated with the complete absence of leptin or leptin
action.83 For example, as described earlier in this review,
individuals without adipose tissue, who also lack leptin, have
ectopic fat deposition and lipotoxicity.30,31 Furthermore, ro-
dent models of either naturally occurring leptin deficiency or
unresponsiveness, or transgenically created lipodystrophy,32
have similar lipotoxic phenotypes. Importantly, administra-
tion of leptin to people with lipodystrophy92 or to rodent
models of leptin deficiency,93 reverses many of the lipotoxic
sequelae. This is due partly to direct effects of leptin on
metabolism, although some of the effects of administered
leptin may be through suppression of hyperphagia. The
importance of leptin for FA metabolism in nonadipose tissue
of obese people who have, in general, increased levels of
leptin, remains to be determined.
Adiponectin
Adiponectin (ACRP30, adipoQ, apM1, or GBP28) was iden-
tified as the product of a gene induced during adipocyte
differentiation.94 It is a 30-kDa protein that is synthesized and
secreted from adipocytes. Adiponectin has an N-terminal
collagenase domain followed by a C-terminal globular do-
main that can undergo homotrimerization.95 In plasma, adi-
ponectin circulates as either a trimer, a hexamer (called the
low molecular weight or LMW form), or as multimeric forms
of 12 to 18 subunits (called the high molecular weight or
HMW form).95 Of note, recent studies suggest that the HMW
form may undergo cleavage to smaller units, including the
trimer, and that the latter may be the active form or be further
cleaved to an even smaller fragment that transduces adi-
ponectin’s signal to cells, particularly to hepatocytes.96 On
the other hand, the globular domain itself (which has not yet
been observed in an in vivo setting) can increase fatty acid
oxidation in mouse muscle,97 probably via activation of
AMPK.98,99 Indeed, transgenic overexpression of the globular
domain of adiponectin in the liver of ob/ob mice improved
total body insulin sensitivity and increased fatty acid oxida-
tion in skeletal muscle.100 To make matters more complex,
studies have indicated that different forms of circulating
adiponectin have affects in specific tissues.99,101 Three puta-
tive receptors for adiponectin have been cloned.102,103 One is
mainly in liver, one in skeletal muscle, and one endothelial
cells and smooth muscle. PPAR␥ agonists increase,104
whereas both tumor necrosis factor-␣ (TNF-␣) and interleu-
kin (IL)-6105 inhibit, adiponectin gene expression.
Adiponectin-deficient mice develop insulin resistance on a
high-fat diet.106,107 Transgenic expression of adiponectin in
adipose tissue resulted in increased plasma levels and inhibi-
tion of hepatic glucose production with improved glucose
tolerance.108 Administration of recombinant adiponectin to
lipodystrophic or obese mice results in reductions in plasma
FA and TG levels,109 whereas transgenic mice with increased
secretion of full-length adiponectin had improved clearance
of an exogenous fat load.108
Adiponectin levels in plasma, which are very high com-
pared with other adipokines, are reduced in obese, insulin-re-
sistant, diabetic, or dyslipidemic subjects.110 In humans,
adiponectin levels are inversely correlated with plasma TG
levels and positively correlated with HDL cholesterol con-
centration, although it is not clear if there are direct links
between adiponectin and plasma lipid levels or these findings
are related to adiponectin’s effects on insulin sensitivity.
However, a recent study suggested a strong relationship
between adiponectin levels and LPL activity in humans,111
and increased adipose tissue LPL activity was present in a
transgenic mouse that secretes increased quantities of full-
length adiponectin from adipose tissue.108 In humans, adi-
ponectin levels are predictive of hepatic steatosis and are
inversely related to hepatic fat content and hepatic insulin
resistance before and after treatment with a PPAR␥
agonist.112
Resistin
Resistin is a 12-kDa protein that is synthesized and secreted
from adipose tissue. It was discovered in mice by searching
 Yu et al
for genes that were suppressed by a PPAR␥ agonist.113
Resistin levels are elevated in both diet-induced obesity and
genetic (leptin or leptin receptor deficient) mouse models of
obesity/diabetes.113 Recombinant resistin decreases insulin
sensitivity in mice, and antibodies against resistin block this
effect. Resistin infusions in rodents during euglycemic hy-
perinsulinemic clamp conditions, caused increased hepatic
glucose production.114 Mice treated with Western-type high-
fat diets had concomitant increases in resistin levels, and
antisense oligodeoxynucleotides that normalized resistin lev-
els also reversed hepatic insulin resistance.115 These results
are consistent with the data obtained from resistin knockout
mice, which despite having no changes in body weight or fat
mass, showed significantly lower fasting plasma glucose
levels when fed with normal chow diet. When fed with
Western-type high-fat diet, the resistin-deficient mice also
showed significantly better glucose tolerance than the wild-
type mice.116 Deletion of the resistin gene was associated
with increased AMPK activity in hepatocytes, decreases in
gluconeogenic enzymes, and decreased hepatic glucose pro-
duction.116 On the other hand, transgenic overexpression of
resistin was associated with increased hepatic glucose pro-
duction and glucose intolerance.117 Of interest, like adiponec-
tin,95 resistin appears to circulate in mice in both trimeric and
hexameric forms, with the smaller form (or possibly the
monomer) being the most biologically active molecule.118
Resistin has more recently been shown to have effects on
lipid metabolism in mice. When adenovirus-mediated over-
expression of resistin was achieved in normal chow-fed mice,
plasma TG levels increased, and this was associated with
increased secretion of TG from the liver.119 LDL cholesterol
also increased whereas HDL cholesterol fell in the mice, and
these changes were associated with reduced expression of the
LDL receptor and apoAI genes, respectively.119 Wistar rats
that had been made “hyper-resistinemic” by adenoviral ad-
ministration also had increased plasma TG levels.120 No
mechanistic studies of lipid metabolism were performed in
the latter study.
The role of resistin in humans is less certain, however.
Clinical studies in humans do not show a consistent link
between resistin levels and either obesity or insulin resis-
tance.4,121,122 There is also controversy regarding the impor-
tance of adipocytes as a source of resistin in human.123,124
Human resistin is only 64% homologous (53% identical with)
with the murine counterpart, and both are members of the
family of resistin like molecules, RELM (also called FIZZ),
which are C-terminal cysteine-rich proteins.124 Given the
diverse roles and tissue specificities of this protein family,
and the low homology between the rodent and human forms,
it is unclear at present whether human resistin plays a similar
role as murine resistin, and if it does, how important human
resistin is in the pathogenesis of the human insulin resistance.
Role of Adipocytokines in Lipid Metabolism
During acute injury or infection, a host of defense responses
are elicited, including changes in the partitioning of lipid-
derived energy that are associated with insulin resistance and
increases in plasma TG and FFA levels. It is believed that
these acute metabolic responses are initiated, at least in part,
Adipocyte Signaling and Lipid Homeostasis 1047
by proinflammatory cytokines. Further, dyslipidemia, insulin
resistance, atherosclerosis, and obesity125 have been linked
with chronic inflammation. Cytokines are produced not only
by immune cells, but also by adipocytes (hence the term
adipocytokine).125,126 In fact, adipose tissue is able to secrete
a range of “acute-phase reactants,” which have been linked,
both epidemiologically and biochemically, to the chronic
disorder, insulin resistance. The demonstration of cytokine
production in adipose tissue suggests that obesity is either
seen by the whole organism as an inflammatory state, or that
adipocytokines are playing a physiological role in attempting
to maintain normal fuel homeostasis.
Tissue Necrosis Factor-␣
TNF-␣ is a 26-kDa transmembrane protein, which is released
into the circulation as a 17-kDa soluble protein after extra-
cellular cleavage by a metalloproteinase.127 TNF-␣ has 2
main receptors, type 1 and 2, which are expressed on many
cells, including adipocytes.128 Although circulating TNF-␣
levels are relatively low and have no clear correlation with
obesity or insulin resistance, tissue expression levels of
TNF-␣ correlate positively with both conditions. In mice,
chronic exposure of cells or whole animals to TNF-␣ induces
insulin resistance, and treatment with soluble forms of TNF-␣
receptors neutralize this effect. Furthermore, mice with tar-
geted gene deletion of TNF-␣ or its receptors showed
increased insulin sensitivity and improved plasma FFA
levels.129
TNF-␣ has multiple effects on lipid metabolism, via both
paracrine effects on adipocytes and effects in the liver. In
adipose tissue, TNF-␣ promotes lipolysis,130 leading to ele-
vation of plasma FA levels. Although there are differences
between murine and human adipocytes regarding mechanistic
details, TNF-␣–induced lipolysis is, in general, mediated by
p44/42 and JNK. These kinases can phosphorylate perilipin,
thereby displacing it from lipid droplets and making TG
accessible to HSL.131 Additionally, TNF-␣ causes reductions
in the expression of genes involved in adipogenesis and
lipogenesis in adipocytes, likely through NF-␬␤–mediated
transcription.132 By contrast, in liver, TNF-␣ increases the
expression of genes involved in de novo fatty acid synthesis
while decreasing expression of those involved in fatty acid
oxidation. It is not surprising, therefore, that TNF-␣ acutely
stimulates VLDL production from liver.133 Increased VLDL
secretion, together with TNF-␣–mediated inhibition of LPL
in adipose tissue,134 results in significant hypertriglyceride-
mia. TNF-␣ impairs insulin signaling as well, probably by
activating Ser/Thr kinases (PKC⑀, PKC␨, Raf1, and IKK-␤)
that act on insulin receptor and IRS molecules, making them
poor substrates for insulin-mediated tyrosine phosphorylation
and signal propagation.135 Hepatic insulin resistance in-
creases apolipoprotein B secretion by reducing intracellular
degradation of this protein.49 Finally, TNF-␣ can affect lipid
metabolism by altering the secretion of other adipokines. For
example, TNF-␣ potently reduces expression of adiponectin
(Acrp30) and increases expression of IL-1 and IL-6.132
Interleukin-6
IL-6 is a protein of 22 to 27 kDa, with various degrees of
glycosylation.136 In contrast to TNF-␣, IL-6 circulates at
1048 Circulation Research May 27, 2005
relatively high levels, and adipocytes contribute ⬇1/3 of the
plasma IL-6.137 Plasma levels of IL-6 correlate positively
with fat mass, insulin-resistant syndrome, and plasma FFA
levels.138,139 Administration of IL-6 to humans results in
elevations of plasma FA and increased FA appearance in
plasma, consistent with increased adipocyte lipolysis of
TG.140,141 Fatty acid oxidation also appears to increase during
IL-6 administration to humans.140 These results are consistent
with the demonstration that an IL-6 receptor, homologous to
the leptin receptor, is present in adipose tissue.4 IL-6 infu-
sions also produce dose-dependent increases in plasma glu-
cose secondary to the development of insulin resistance or
increased levels of glucagon.142 Studies in hepatocytes
showed that IL-6 is able to impair insulin signaling by
downregulation of IRS and upregulation of SOCS-3 (suppres-
sor of cytokine signaling 3), a negative regulator of insulin
signaling. Recently, upregulation of SOCS-3 by IL-6 was
affirmed in human skeletal muscle and adipose tissue.143
Moreover, IL-6 inhibits adiponectin production in adipo-
cytes,144 an action that may contribute to IL-6 –induced
hepatic insulin resistance. Finally, IL-6 suppresses LPL
activity in adipose tissue.145
IL-6 signaling is complex, however, because of its appar-
ently opposite role in the central nervous system.4 Central
administration of IL-6 in rodents causes increased energy
expenditure, resulting in decreased body fat. This is consis-
tent with the negative correlation between IL-6 levels in the
central nervous system and body fat mass observed in
overweight human subjects.146 The existence of a powerful
central action of IL-6 may be used to explain the phenotype
of the IL-6 knockout mice. Thus, it was reported that these
mice were actually obese, leptin resistant, glucose intolerant,
and in the females, hypertriglyceridemic and hypercholester-
olemic147: phenotypes opposite to what would be expected
from the lack of peripheral action of IL-6. Central replace-
ment of IL-6 in these animals partially reversed obesity,
whereas peripheral administration of IL-6 had no effect.147 It
should be noted, however, that the obese and insulin-resistant
phenotypes in IL-6 – deficient mice were not confirmed in a
recent report,148 and the reason for the different findings was
not clear.
Secretion of Apolipoproteins by Adipocytes
It is not totally surprising that adipose tissue, which not only
contain the large majority of the body’s TG stores, but also
the largest store of cholesterol in the body, synthesizes and
secretes several apolipoproteins. ApoE is a 34-kDa protein
that is well known as a key apolipoprotein involved in both
secretion and uptake of lipoproteins by tissues and in choles-
terol efflux from cells.149 Expression of apoE by adipocytes,
and regulation of that expression by cellular cholesterol, were
demonstrated over a decade ago.150 Consistent with the latter
finding, and with prior studies in macrophages indicating a
role for apoE in cholesterol efflux, recent studies have shown
that the apoE gene is a target of adipocyte liver X receptors
(LXR).151 Potentially relevant to this review are recent
findings indicating that PPAR␥ agonists increased apoE
mRNA in human adipose tissue and 3T3-L1 cells.152 Addi-
tionally, although incubation of cultured 3T3-L1152 or SW872
liposarcoma cells153 with insulin did not affect apoE mRNA,
apoE secretion fell in the liposarcoma cells exposed to
increasing insulin concentrations.153 If adipose apoE secre-
tion is responsive to insulin in otherwise insulin-resistant
adipocytes, then adipocyte apoE secretion might be reduced
in states of whole-body hyperinsulinemia. This could lead to
defective cholesterol efflux from fat.
Two other apolipoproteins, apoC-I and apoD, have also
been identified as adipocyte products.153,154 ApoC-I is a
6.6-kDa protein that plays a role in regulating receptor-
medicated removal of lipoproteins from plasma.10 In SW872
liposarcoma cells, expression of apoC-I increased with in-
creasing cell lipids, and this was associated with increased
apoC-I secretion. Insulin treatment, however, reduced both
apoC-I mRNA levels and apoC-I secretion into the media.153
The relevance of these findings remains unclear, but the fact
that transgenic mice overexpressing apoC-I have defects in
fatty acid uptake by adipose tissue155 and resistance to
obesity156 suggests that in hyperinsulinemic states, reduced
apoC-I synthesis and secretion could contribute to obesity.
ApoD is a 6.6-kDa protein that is a member of the lipocalin
family of lipid transporters.154 ApoD has recently been
identified as a target for LXR␣ in adipocytes, suggesting a
role in cholesterol efflux.157 What role apoD plays in adipo-
cyte function in vivo and whether apoD might be relevant to
adipocyte dysfunction in insulin-resistant states remain to be
determined.
Summary
In this review, we have focused particularly on how unregu-
lated secretion of FA from insulin-resistant adipocytes can
affect lipid metabolism in liver, muscle, and pancreatic ␤
cells. It is clear from published literature that dysregulated
partitioning of FA between storage sites (adipocytes) and
sites of utilization (muscle, liver, and ␤ cells) upsets lipid
homeostasis in the latter tissues, with deleterious outcomes,
including TG accumulation and insulin resistance. We did not
mean to suggest, however, that adipose tissue insulin resis-
tance is the only cause of the insulin resistance present either
in those other sites, or in the whole body, in rodents or people
with the metabolic syndrome. Although we believe that
adipose tissue insulin resistance plays a key role in the
“typical” insulin resistance found in obese humans, it is clear
from several mouse models that muscle158 and liver51 can be
the sites of primary insulin resistance, with the possibility for
subsequent secondary insulin resistance in the other tissues,
including adipose tissue. Further, the basis of adipocyte
insulin resistance is very poorly defined. Indeed, even the
roles of insulin receptors and PPAR␥, 2 key proteins involved
in energy storage by adipose tissue, are complex and incom-
pletely understood. For example, adipocyte-specific targeted
deletion of the insulin receptor (FIRKO mice) results in
smaller mice with less body fat, increased whole-body insulin
sensitivity, and resistance to age- and obesity-related insulin
resistance, despite a clear lack of insulin stimulated glucose
and lipid metabolism in adipocytes.159 However, the FIRKO
mice do not have increased plasma FA or TG levels, have
normal basal and isoproterenol-stimulated lipolysis, and have
increased plasma levels of both leptin and adiponectin; all
 Yu et al
factors that could protect against systemic insulin resistance
in this complicated model. Overall, mouse models of tissue-
specific loss of insulin receptors or glucose transporters are
indicative of this species’ ability to shift metabolic substrates
from an insulin-resistant tissue to unaffected tissues.160 We
propose that when humans are unable to store energy nor-
mally, whether because of the quantitative or qualitative
absence of adequate adipose tissue, they also seem to transfer
that energy, in the form of FA, to alternative sites such as
liver, muscle, and ␤ cells. Whether the accumulation of FA at
those sites is adequate to produce the detrimental metabolic
sequelae we described in detail in this review or whether
concomitant dysregulation of the secretion of adipokines and
adipocytokines is required is not clear. What is clear, how-
ever, is that the inability to store energy in adipocytes leads to
abnormal lipid metabolism and potentially insulin resistance,
inflammation, and cell death in the alternative storage sites.
Acknowledgments
This work was supported by the following grants: Ginsberg: R01
HL55638, R01 HL73030; Yu: K08 DK60530.
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