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Adipose Tissue and Insulin Resistance
Stephen E. Borst
Abstract
Adiposity, especially visceral adiposity, is an important risk factor for the development of insulin
resistance and type 2 diabetes. In addition to its role in storing energy, adipose tissue also secretes
into the circulation a number of hormones and other factors that can alter the response to insulin in
distant tissues, such as liver and muscle. Many of these factors are cytokines, which have been associated with the immune system.
Fat-derived hormones that can enhance insulin signaling include leptin, adiponectin, and possibly visfatin. Those impairing insulin signaling include tumor necrosis factor-F, resistin, and several
of the interleukins. Obesity has also been identified as a low-grade inflammatory state. Several possible mechanisms are discussed whereby rapid growth of adipose tissue might trigger a local inflammatory response. It is suggested that this inflammatory response and associated release of cytokines
may constitute the link between obesity and insulin resistance.
Key Words: Tumor necrosis factor; resistin; adiponectin; interleukins; free fatty acids; subcutaneous fat; visceral fat; insulin signaling.
1. INTRODUCTION
Obesity and type 2 diabetes are the most common metabolic diseases in Western
society, together affecting as much as half of the adult population (1). Not only is the
prevalence of these conditions high, but it also continues to increase. Insulin resistance
is a prediabetic condition, characterized by a failure of target organs to respond normally to insulin. Insulin resistance includes a central component (incomplete suppression of hepatic glucose output) and a peripheral component (impaired insulin-mediated
glucose uptake in skeletal muscle and adipose tissue) (2). When increased insulin
secretion is no longer sufficient to prevent hyperglycemia, the subject progresses from
insulin resistance to type 2 diabetes. Insulin resistance is associated with other conditions such as central obesity, hypertension, and dyslipidemia, all risk factors for cardiovascular disease. The constellation of these metabolic abnormalities has been termed
metabolic syndrome.
Obesity is a well-recognized risk factor for the development of insulin resistance and
metabolic syndrome. In addition to the total amount of fat, distribution of adipose tissue
is also important, with most studies concluding that visceral fat contributes considerably
more to insulin resistance than does subcutaneous fat (3). However, one report, by Misra
et al., documented a robust correlation between posterior abdominal subcutaneous fat
From: Nutrition and Health: Adipose Tissue and Adipokines in Health and Disease
Edited by: G. Fantuzzi and T. Mazzone © Humana Press Inc., Totowa, NJ
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and insulin resistance (4). Underscoring the importance of visceral fat is the report by
Klein et al. that liposuction, resulting in a substantial reduction of subcutaneous fat, did
not enhance insulin responsiveness in insulin-resistant subjects (5). In rats, we (6) and
others (7) have found that surgical removal of visceral fat reverses insulin resistance.
Traditionally, adipose tissue has been regarded largely as a depot for stored fat. More
recently, it has become clear that adipose tissue plays an active role in energy metabolism and is the source of hormones, cytokines, and metabolites that play an important
role in whole-body metabolism (8). The role of these substances may be either autocrine
or endocrine. Adipose tissue, especially visceral fat, is the source of a number of substances that might play a role in the development of insulin resistance. Among the latter
are tumor necrosis factor (TNF)-F, adiponectin, interleukin (IL)-6, resistin, and free fatty
acids. The difference in the metabolic effects of visceral versus subcutaneous fat may be
attributed both to differences in the hormones secreted by the two types of fat and to the
fact that hormones secreted by visceral fat reach the liver in high concentration. The latter is due to the fact that visceral fat drains into the portal circulation, whereas subcutaneous fat drains into the systemic circulation (8). This review will focus on the regulation
of insulin responsiveness by adipokines and on evidence supporting the hypothesis that
these hormones play a role in the pathophysiology of insulin resistance.
2. OBESITY AS AN INFLAMMATORY CONDITION
Obesity produces a state of low-grade inflammation, characterized by elevated circulating concentrations of acute-phase proteins, such as C-reactive protein (CRP), plasminogen activator inhibitor (PAI)-1, and fibrinogen (9,10). CRP is elevated moderately in obese
men and highly in obese women (11). Hak et al. reported that in a group of healthy
middle-aged women, CRP was approximately threefold higher in the group whose body
mass index (BMI) was in the upper half (9). The mean CRP concentration in the upperBMI group was 1.15 mg/L, around the threshold of a clinically elevated level (11).
There are at least two theories as to why obesity should cause a state of inflammation. First, the growth—especially the rapid growth—of adipose tissue may cause local
hypoxia due to inadequate perfusion and result in the generation of angiogenesis factors
such as vascular endothelial growth factor (VEGF) and 11G-hydroxysteroid dehydrogenase type 1. Overexpression of the latter enzyme in rodents has been shown to cause
adipose production of the inflammatory cytokines resistin and TNF-F, both cytokines
being implicated in the development of insulin resistance (12). A second possibility is
that rapid expansion of adipose tissue results in the differentiation of preadipocytes into
macrophage-like cells (13). It is well-known that obesity is accompanied by an overexpression of TNF-F in adipose tissue. Weisberg et al. have recently shown that obesity
is accompanied by an increased number of macrophages in adipose tissue, but not in
liver or muscle (14). The overexpression of TNF-F that occurs in adipose tissue of obese
humans occurs exclusively in macrophages.
3. ROLE OF LEPTIN RESISTANCE IN OBESITY AND INSULIN
RESISTANCE
Leptin is produced by adipocytes and secreted into the blood. In the healthy state, the
circulating leptin concentration varies in proportion to adipose mass. Activation of leptin
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283
receptors in the hypothalamus decreases food intake and increases energy expenditure
via uncoupling proteins (UCPs) in fat and muscle. UCPs are mitochondrial proteins that
allow for oxidation of substrates with the production of heat, rather than storage of
energy in the form of ATP. Thus leptin serves as part of an “adipostat” mechanism,
whereby increased adiposity sets in motion responses that will eventually reduce
adiposity. In 1994, Friedman et al. discovered that ob/ob mice are leptin-deficient and
lose weight following leptin treatment (15). However, obese humans are typically
leptin-resistant and have higher-than-normal circulating concentrations of leptin. Leptin
resistance in humans has two components: impaired transport of leptin across the
blood–brain barrier and impaired signaling via hypothalamic leptin receptors (16).
In addition to its function as a direct regulator of adiposity, leptin is also an insulinsensitizing hormone (17,18). Thus, the reduced responsiveness to leptin that accompanies obesity and may play a role in causing obesity also plays a role in causing insulin
resistance in the brain. Insulin receptors in the hypothalamus play an important role in
glucose homeostasis (18). Primate studies have shown that direct delivery of insulin to
the brain reduces feeding (18); rodent studies have shown that intracerebroventricular
administration of insulin not only reduces food intake, but also suppresses hepatic glucose output (19,20). There is growing evidence that the link between leptin resistance
and insulin resistance is suppressor of cytokine signaling (SOCS)3, a molecule that
impairs signaling of both leptin and insulin (21), and one that is suppressed by leptin
(22). Mice with reduced neuronal expression of SOCS have enhanced sensitivity to
leptin and insulin and are protected against diet-induced obesity (23).
4. ROLE OF TNF-F IN LINKING OBESITY TO INSULIN RESISTANCE
TNF-F was first shown by Hotamisligil et al. to be overexpressed in adipose tissue
from several strains of obese rodents (24). Weisberg et al. have shown that macrophages
are the main source of TNF-F in adipose tissue (14). TNF-F expression is higher in
visceral fat (VF) of rodents than in subcutaneous (sc) fat (25). In addition, TNF-F has
been shown to impair insulin signaling in cultured cells by three separate molecular
mechanisms. TNF-F activates serine/threonine kinases that phosphorylate and impair the
function of key elements in the insulin signaling pathway (26). First, TNF-F mediates
a serine phosphorylation of IRS-1 (27). This alteration impairs insulin signaling by
making IRS-1 resistant to subsequent insulin-stimulated tyrosine phosphorylation.
Second, TNF-F phosphorylates and activates a protein tyrosine phosphatase that normally
terminates insulin action, thus playing a role in the self-limiting nature of insulin signaling (28). Third, TNF-F phosphorylates and inactivates the protein phosphate PP-1 at site
2, resulting in its inactivation (29). This action of TNF-F opposes the action of insulin,
whereby glucose storage is promoted by phosphorylating PP-1 at site 1 and activating it.
The above findings led to the popular theory that TNF-F of adipose origin is secreted
into the circulation, from where it reaches targets such as muscle and liver and causes
insulin resistance. However, circulating levels of TNF-F are very low compared with the
concentrations required to induce insulin resistance when infused into rats (30) and tissue levels of TNF-F are several orders of magnitude higher than circulating levels (31).
Whereas some studies have shown that circulating TNF-F is elevated in obese and
insulin-resistant subjects (32), others have not (33).
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We hypothesize that locally produced TNF-F may contribute to insulin resistance in one
of two ways. First, obesity may cause insulin resistance in by increasing TNF-F expression
in targets such as muscle. Support for this concept is our report that diet-induced obesity in
rats is accompanied by reduced insulin-stimulated glucose transport in skeletal muscle,
together with an increase in muscle expression of TNF-F (34). Alternatively, obesity may
increase TNF-F expression in adipose tissue, leading to the release into the circulation of
other cytokines that are capable of causing systemic insulin resistance.
5. ROLE OF ADIPONECTIN IN INSULIN RESISTANCE
Adiponectin is an insulin-sensitizing hormone produced exclusively by adipocytes
(35). There is a strong and positive correlation between serum adiponectin and insulin
responsiveness. In a group of normal and obese subjects, Weyer et al. studied the relationship between serum adiponectin and the glucose disposal rate, measured during
hyperinsulinemic euglycemic glucose clamp studies (36). Serum adiponectin varied
over a fivefold range, correlated positively with glucose disposal, and accounted for
approx 35% of the variance in insulin responsiveness.
Adiponectin increases oxidation of free fatty acids and reduces postprandial elevation
of nonesterified fatty acids (NEFAs) in mice (37). Adiponectin circulates at concentrations
in the low Rg/mL range, whereas most cytokines produced by adipose tissue are in the
pg/mL range (35). In rodents, adiponectin expression is considerably higher in VF than in
sc fat (38), and adiponectin secretion by VF has an inverse relationship with VF mass—
i.e., the larger the mass of VF, the less adiponectin is secreted. Serum adiponectin is low
in obese humans (39) and increases following weight loss (40). Yamauchi et al. have
shown that administration of adiponectin to obese rats on a high-fat diet reduces weight
gain and prevents the development of hepatic insulin resistance (41). The mechanism by
which adiponectin enhances insulin responses has not been well-studied, but may involve
opposing of TNF-F-induced activation of the transcription factor NFPB (42).
6. ROLE OF RESISTIN IN INSULIN RESISTANCE
Resistin is a recently discovered polypeptide that is secreted by mouse adipocytes
and has been implicated in the development of insulin resistance. Resistin was first
described in 2001, when a search for genes that are induced during adipocyte differentiation but downregulated in mature adipocytes during exposure to thiazolidinediones
led to the discovery of a protein the investigators named resistin, for “resistance to
insulin” (43). Administration of resistin in normal mice impairs glucose tolerance and
insulin action. Furthermore, immunoneutralization of resistin improved blood glucose
and insulin action in animal models of obesity-induced insulin resistance. In rodents,
administration of thiazolidinedione drugs reverses insulin resistance. These drugs also
reduce gene and protein expression of resistin in some studies (44) but not in others (45).
These initial data suggested that resistin, at least in part, may explain how adiposity leads
to insulin resistance and may also explain the antidiabetic effects of thiazolidinedione
drugs. The molecular mechanism for the action of resistin is unknown. A recent study
in mice suggested that resistin selectively impairs the inhibitory action of insulin on
hepatic glucose production (44). However, the role of resistin in obesity-associated
insulin resistance has become controversial because the biology of resistin is different
Chapter 21 / Adipose Tissue and Insulin Resistance
285
in humans than in rodents and additional evidence has suggested that obesity and insulin
resistance are associated with decreased resistin expression (45–47).
Whether resistin is expressed in human adipose tissue is not clear. McTernan et al.
found such expression and reported that resistin is relatively highly expressed in the
omental visceral fat and the abdominal subcutaneous fat, with lower expression in
subcutaneous fat on the thigh (48). This finding is in contrast to the findings of Savage
et al. and Nagaev et al., who did not detect resistin in human adipose tissue (49,50).
Whereas resistin is expressed mainly in adipocytes in mice (43), Fain et al. reported that
most of the resistin secreted by human fat explants is derived from nonadipocytes (51).
The reason for the differences in these studies is unclear. Human resistin is only 59%
similar to the mouse protein, and this may portend important differences in the
endocrine functions of adipocytes and resistin between rodents and humans (52).
Furthermore, insulin and TNF-F, both elevated in obesity, have been found to inhibit
resistin expression, which may explain the low levels of resistin found in the recent studies of obesity diabetes.
The initial suggestion that resistin may be the link between obesity and insulin resistance is being challenged. The role of resistin in normal and abnormal physiology remains
elusive. Studies from knockout mice and better characterization of resistin changes in
humans should help determine whether this adipokine is a cause of insulin resistance or
simply a bystander. Also, it will important to understand the similarities and differences
between mouse and human resistin and mechanisms of obesity-related insulin resistance.
7. ROLE OF IL-6 IN INSULIN RESISTANCE
IL-6 is a pleiotropic circulating cytokine that has important roles in inflammation,
host defense, and response to tissue injury (53). It is one of several proinflammatory
cytokines with a proposed role in the development of insulin resistance. IL-6 is secreted
by many cell types, including immune cells, fibroblasts, endothelial cells, skeletal muscle, and nonadipocyte cells in adipose tissue, and circulates as a variably glycosylated
22- to 27-kDa protein (2).
IL-6 is released from contracting skeletal muscle, causing the serum concentration to
increase as much as 100-fold (54). IL-6 increases hepatic glucose production when
administered to human subjects, and there is evidence to suggest that the release of IL-6
from exercising muscle mediates the early phase on exercise-induced hepatic glucose
output. The fact that IL-6 opposes insulin action in the liver has led to speculation that
its oversecretion may play a role in insulin resistance. In the liver, IL-6 causes release
of NEFAs and is the primary stimulator of for production of acute phase proteins (55).
Administration of IL-6 in healthy volunteers induced dose-dependent increases in blood
glucose (56), probably by inducing resistance to insulin action. In vitro, IL-6 has been
shown to impair insulin signaling by several distinct molecular mechanisms (57).
Weight loss significantly decreases IL-6 levels in both adipose tissue and serum (58).
Genetic studies have also demonstrated a high level of correlation between insulin
resistance and IL-6 gene polymorphism (59). Besides its glucoregulatory effect, IL-6
increases circulating free fatty acids (FFA) from adipose tissue with their well-described
adverse effects on insulin sensitivity (60). Because visceral depots drain into the portal
circulation, the metabolic effects of IL-6 on the liver become important. Indeed, there is
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evidence to suggest that IL-6 inhibits insulin receptor signal transduction in hepatocytes
that is mediated, at least in part, by induction of SOCS3 (61). IL-6 may also exert its
adverse effects, at least in part, by decreasing adipose secretion adiponectin (62).
Although much evidence implicates IL-6 in insulin resistance, there is some conflicting evidence. In a recent study, acute IL-6 administration did not impair glucose homeostasis in healthy individuals (63). Moreover, IL-6-deficient mice were not protected
from development of obesity and glucose intolerance (64). Circulating IL-6 is elevated
approximately twofold in obese, insulin-resistant subjects, but although the association
is statistically significant, the relationship is not a strong one, accounting only for approx
7% of the variance in insulin responsiveness (33,65,66). Although VF produces two- to
threefold more IL-6 than does sc fat, adipose tissue is the source for only about 30% of
circulating IL-6 in humans (38), with the majority of adipose tissue-derived IL-6 coming
from stromal immune cells and not adipocytes (67).
In summary, a body of evidence indicates that IL-6 of adipose origin may play a role
in systemic insulin resistance, although there is also some evidence to the contrary.
8. OTHER POSSIBLE MEDIATORS OF INSULIN RESISTANCE
Visfatin is a recently discovered adipokine that is produced by adipocytes (68), and
is expressed in visceral fat at much higher levels than in subcutaneous fat (69). Serum
visfatin increases with VF, but not sc fat, in humans and mice. Visfatin has been shown
to have insulin-sensitizing properties when administered to insulin-resistant mice. Mice
that are heterozygous for a targeted mutation in the visfatin gene display a small impairment in glucose tolerance, whereas homozygous mice die in utero. Visfatin binds to the
insulin receptor and activates downstream signaling, but does not compete for binding
with insulin. Visfatin has the ability to stimulate glucose transport in cultured muscle
and adipose cells and to inhibit glucose output in cultured hepatocytes.
Apart from cytokines, the most important candidate for linking obesity to insulin
resistance is circulating nonesterified (or free) fatty acids. Reaven et al. reported that
type 2 diabetes is associated with elevations in both fasting and postprandial NEFAs
(70). Boden et al. have shown that both acute infusion and chronic elevations of NEFAs
can decrease insulin-stimulated glucose disposal in humans (71). It is proposed that
increased hydrolysis of NEFAs leads to increased diacyl glycerol, which in turn activates
isoforms of protein kinase C (PKC). Although activation of PKC-_ is a part of normal
insulin signaling, activation of PKC-V has been shown to impair insulin signaling (72).
Muscle biopsies from insulin-resistant subjects display serine/threonine phosphorylation of the insulin receptor, an impairment that TNF-F does not cause in cultured cells
(73). Current evidence suggests that serine/threonine phosphorylation of IRs is mediated by the theta isoform of protein kinase C, an enzyme that may be activated by an
increase in serum FFA (74). Additionally, Bjorntorp has hypothesized that increased
visceral fat causes hepatic insulin resistance by a “portal” mechanism, where a higher
concentration of NEFAs reach the liver from omental fat (75).
9. CONCLUSIONS
Table 1 lists candidate adipokines that may potentially link obesity with insulin
resistance. Such candidates should meet several criteria. The adipokine should have a
287
Enhancement
Leptin
Elevated in rodent models of
genetic and diet-induced
obesity
May be elevated in human
obesity and insulin resistance
Dramatic elevation in obese
humans (54)
Serum adiponectin is low in
obese humans (37) and
increases following weight
loss (39)
Increased in human visceral
adiposity (64)
High in obese humans, because
of leptin resistance
Change in blood
concentration
Adipocytes (2)
Adipocytes (68)
Adipose tissue macrophages
(14), liver and muscle (26)
Non-adipocyte fat cells, immune
cells, skeletal muscle (2)
Adipocytes (37)
Mouse adipocytes (43), human
non-adipocyte fat cells (51)
Tissue expression
Higher in SCF of humans (8)
Higher in VF of humans (66)
Higher in VF of rodents (38)
Higher in VF of humans (38)
Markedly higher in VF of rodents
(25). Equal in VF and SCF
of humans (48)
Higher in VF of rodents (25)
Expression in
VF vs SCF
aCandidate proteins should meet the following criteria: (1) the hormone should have an effect on insulin responses, (2) blood levels should be appropriately
elevated of reduced in obesity and insulin resistance, (3) a significant fraction of circulating hormone should derive from adipose tissue and (4) production of the
hormone should be higher in visceral fat (VF) than in subcutaneous fat (SCF).
Enhancement
Impairment
IL-6
Visfatin
Impairment
TNF-F
Enhancement
Impairment
Resistin
Adiponectin
Effect on
insulin response
Adipokine
Table 1
Circulating Proteins Secreted by Adipose Tissue and That May Link Obesity to Insulin Resistance and Diabetes
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major effect on insulin responsiveness; the circulating level should correlate to insulin
responsiveness and increase or decrease appropriately in animal models and experimental conditions. A significant fraction of the circulating cytokine should be of adipose
origin and expression should be higher in visceral fat than in subcutaneous fat.
Based on these criteria, there is strong evidence in favor of adiponectin as a link
between obesity and insulin resistance. Adiponectin is an insulin-sensitizing hormone
that is produced almost exclusively in fat, with higher expression in visceral fat. Serum
adiponectin is strongly and inversely correlated to insulin resistance and fat mass and
increases after weight reduction.
There is evidence both for and against the role of IL-6 in linking obesity to insulin
resistance. IL-6 has the ability to impair insulin responses and is elevated in obesity, but
circulating levels correlate only weakly to insulin responsiveness.
The case for resistin is strong in rodents, but weaker in humans. Resistin is preferentially expressed in visceral fat of mice and is elevated in rodent models of genetic and
diet-induced obesity. However, resistin biology may be different in humans, and some
studies suggest that it is not expressed in human adipose tissue. Leptin is an insulinsensitizing hormone that is elevated in serum of obese subjects owing to leptin resistance.
This phenomenon is similar to the elevation of insulin in insulin resistance. Leptin plays
a prominent role in the development of obesity. Leptin resistance may also underlie
insulin resistance in the brain.
TNF-F is overexpressed in tissues of obese and insulin-resistant animals. TNF-F
circulates at low levels; some studies have found serum levels to be elevated in
insulin-resistant subjects, while others have not. TNF-F impairs insulin responses in
muscle fat and liver by well-established molecular mechanisms. Most evidence suggests that TNF-F plays a paracrine or autocrine role in linking obesity to insulin
resistance.
Visfatin is a recently discovered insulin-sensitizing hormone that increases with visceral fat mass. Although less is known about visfatin than other adipokines, the latter
finding argues against its role as a link between obesity and insulin resistance.
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