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Obesity is associated with an array of health problems in adult and pediatric populations. Understanding the pathogenesis of
obesity and its metabolic sequelae has advanced rapidly over the past decades. Adipose tissue represents an active endocrine
organ that, in addition to regulating fat mass and nutrient homeostasis, releases a large number of bioactive mediators
(adipokines) that signal to organs of metabolic importance including brain, liver, skeletal muscle, and the immune system
thereby modulating hemostasis, blood pressure, lipid and glucose metabolism, inflammation, and atherosclerosis. In the present
review, we summarize current data on the effect of the adipose tissue-derived hormones adiponectin, chemerin, leptin, omentin,
resistin, retinol binding protein 4, tumor necrosis factor- and interleukin-6, vaspin, and visfatin on insulin resistance.
Online address: http://www.molmed.org
doi: 10.2119/2008-00058.Rabe
INTRODUCTION
Adipose tissue is composed of
adipocytes embedded in a loose connective tissue meshwork containing adipocyte precursors, fibroblasts, immune
cells, and various other cell types. Adipose tissue was traditionally considered
an energy storage depot with few interesting attributes. Due to the dramatic rise
in obesity and its metabolic sequelae
during the past decades, adipose tissue
gained tremendous scientific interest. It
is now regarded as an active endocrine
organ that, in addition to regulating fat
mass and nutrient homeostasis, releases
a large number of bioactive mediators
(adipokines) modulating hemostasis,
blood pressure, lipid and glucose metabolism, inflammation, and atherosclerosis.
Table 1 summarizes the adipokines discussed in this review article, the interplay between adipokines, and their effects on glucose homeostasis.
ADIPONECTIN
Adiponectin expression occurs from
an intermediate stage of adipogenesis
LR isoforms aeb
Unknown
Unknown
unknown
(RAR, RXR, cell surface
receptors?)
TNFR, IL-6R/gp130
Leptin
Omentin
Resistin
Visfatin/PBEF/Nampt
Metabolic function
Abbreviations in table: AdipoR1, adiponectin receptor 1; AdipoR2, adiponectin receptor 2; CMKLR1, chemokine like receptor-1; IL-6R, interleukin-6 receptor; IRS-1,
insulin receptor substrate-1; LR, leptin receptor; Nampt, nicotinamide phophoribosyltransferase; PBEF, pre-B cell colony-enhancing factor; RAR, retinoic acid
receptor; RXR retinoic acid-X receptor; TNFR, Tumor necrosis factor- receptor; vaspin, visceral adipose tissue-derived serine protease inhibitor.
b
LRb is restricted to the hypothalamus, brainstem and key regions of the brain which control feeding, energy balance and glucose metabolism.
c
Effects likely to be mediated through inhibition of a yet-unknown protease.
d
Effects mediated through nicotinamide adenine dinucleotide biosynthetic activity.
Vaspin
Unknown
Unknown
CMKLR1
Chemerin
Receptor
Adiponectin
Adipokine
REVIEW ARTICLE
ponectin was proposed to be the biologically active form of the hormone (37),
and, although not unchallenged (38),
was shown to be superior to total adiponectin in predicting insulin resistance
and the metabolic syndrome trait cluster
(3941). Adiponectin expression and secretion was demonstrated to be upregulated by thiazolidinediones (TZDs)
(4244), and HMW adiponectin is the
predominant form of adiponectin increased by TZDs (37).
Adiponectins effects on glucose metabolism are mediated through two distinct receptors termed adiponectin receptor 1 (AdipoR1) and adiponectin receptor
2 (AdipoR2). AdipoR1 is expressed ubiquitously, whereas AdipoR2 is expressed
most abundantly in the liver (45). Similar
to adiponectin, expression of both receptors was decreased in mouse models of
obesity and insulin resistance (46,47).
Yamauchi et al. (47) reported that liverspecific adenoviral expression of AdipoR1 in leptin-receptor deficient db/db
mice resulted in activation of 5AMPactivated protein kinase (AMPK), leading to reduced expression of genes encoding hepatic gluconeogenic enzymes
such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1, and of
genes encoding molecules involved in lipogenesis, such as sterol regulatory
element-binding protein 1c. Hepatic expression of AdipoR2 increased expression of genes involved in hepatic glucose
uptake such as glucokinase, and of peroxisome proliferator-activated receptor-
(PPAR-) and its target genes such as
acyl-CoA oxidase and uncoupling protein 2. Activation of AMPK reduced endogenous hepatic glucose production,
while expression of both receptors increased fatty acid oxidation, decreased
hepatic triglyceride content and improved insulin resistance. Conversely,
targeted disruption of AdipoR1 resulted
in the abrogation of adiponectin-induced
AMPK activation, and in increased endogenous glucose production and insulin resistance. Knockout of AdipoR2
caused decreased activity of PPAR- signaling pathways and insulin resistance.
ADIPOKINES AND IR
ciated significantly with BMI, triglycerides, and blood pressure (62). Further
studies are needed to determine the
physiological role of chemerin in glucose
metabolism, and to identify chemerins
target tissues as well as relevant signal
transduction pathways.
LEPTIN
Since its identification in 1994, leptin
has attracted much attention as one of
the most important signals for the regulation of food intake and energy homeostasis (6769). Hypothalamic as well as
brain stem nuclei play a critical role in
integrating the information on absorbed
food, on the amount of energy stored in
the form of fat and on blood glucose levels to regulate feeding, energy storage, or
expenditure. Leptin receptor activation at
these sites leads to repression of orexigenic pathways (for example, those involving neuropeptide Y [NPY] and
agouti-related peptide [AgRP]) and induction of anorexigenic pathways (such
as those involving pro-opiomelanocortin
[POMC] and cocaine and amphetamineregulated transcript [CART]) via Janus
kinase (JAK)-signal transducers and activators of transcription (STAT) and
IRS/phosphoinositide-3 kinase (PI3K)
signaling (70). Although changes in food
intake and total body fat clearly can affect insulin sensitivity in peripheral tissues, several observations suggested that
leptin regulation of glucose homeostasis
occurs independently of its effects on
food intake through central and peripheral mechanisms. Hypothalamic arcuate
nucleus (ARC)-specific expression of leptin receptor in leptin receptor-deficient
mice resulted in a modest reduction of
food intake and body fat mass, yet normalized blood glucose and insulin levels
(71). ARC-specific restoration of leptin
receptor in obese, leptin receptordeficient Koletsky rats markedly improved insulin sensitivity via a mechanism that was not dependent on reduced
food intake, but was attenuated by intraventricular infusion of a PI3K inhibitor
(72). ARC-directed expression of a constitutively active mutant of protein kinase B,
REVIEW ARTICLE
ADIPOKINES AND IR
versely, administration of the Nampt reaction product nicotinamide mononucleotide (NMN) resulted in an amelioration of these defects.
In summary, current data suggest that
adipose tissue as a natural source of
eNampt/visfatin/PBEF may regulate
-cell function through secretion of
eNampt and extracellular biosynthesis
of NMN.
ADIPOKINE INTERPLAY
Insulin resistance should be conceptualized in a very broad manner that takes
into account the interplay between nutrition, glucose, insulin and adipokines in
various tissues of metabolic importance.
Interactions between distinct adipokines
add additional complexity to the picture
(Table 1, Figure 1). Current data on
adipokine interplay are rather sparse
and, in part, contradictory due to examination of different in vitro (different cell
types) and in vivo (different species)
models.
Adiponectin and TNF- control each
others synthesis and activity, thus creating a balanced physiologic situation
(164). Overnutrition results in activation
of inflammatory pathways causing a critical imbalance leading to decreased expression of adiponectin. TNF- and IL-6
play a key role in the regulation of many
adipokines. TNF- was reported to
downregulate RBP4 production in
human adipocytes (181). Expression of
leptin (182,183), resistin (115), and
visfatin/PBEF/eNampt (184) is increased
by TNF- and IL-6. Conversely, leptin
(185), resistin (116118), and visfatin/
PBEF/eNampt (186) upregulate the production of TNF- and IL-6, suggesting
that these adipokines could trigger or
participate in the inflammatory process
through direct paracrine and/or autocrine actions. Leptin, however, also was
reported to suppress the expression of resistin and RBP4 (92,187,188), and to increase adiponectin expression in leptindeficient ob/ob mice (188,189). Chemerin
and vaspin, like adiponectin, were
shown to have antiinflammatory properties. Chemerin inhibited the production
REVIEW ARTICLE
5.
6.
7.
8.
9.
Figure 1. Obesity, adipokines and insulin resistance. Murine resistin is expressed in white adipose tissue, whereas in humans, resistin is mainly produced by peripheral-blood mononuclear cells. Green arrows depict stimulation, red lines suppression of gene expression.
release of adipokines, leading to CNSmediated skeletal muscle and hepatic insulin resistance (Figure 1). Understanding of the diverse effects of distinct
adipokines and the interactions between
these bioactive mediators is still incomplete. Unraveling the pathophysiological
roles of adipokines in obesity-induced
diseases likely will result in new pharmacotherapeutic approaches.
CONCLUSION
Obesity has reached dramatic proportions affecting more than 1 billion adults
worldwide (190). The epidemic of obesity also affects children becoming overweight at progressively younger ages.
Obesity is associated with an array of
health problems including insulin resistance and type 2 diabetes, fatty liver disease, atherosclerosis, airway diseases, degenerative disorders, and various types
of cancer. Our understanding of the
pathogenesis of obesity and its metabolic
sequelae has advanced significantly over
the past decades. Environmental factors,
such as sedentary lifestyle and increased
calorie intake, in combination with an
unfavorable genotype, are responsible
for the epidemic of obesity. Excess visceral fat accumulation results in altered
ACKNOWLEDGMENTS
This work was supported by a grant
from the Deutsche Forschungsgemeinschaft (BR 2151/4-1 to UCB).
10.
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DISCLOSURE
The authors have nothing to disclose.
16.
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