The Metabolic Syndrome
Fat as an Endocrine Organ: Relationship to the Metabolic Syndrome

https://doi.org/10.1097/00000441-200512000-00005Get rights and content

ABSTRACT:

Obesity and the metabolic syndrome have both reached pandemic proportions. Together they have the potential to impact on the incidence and severity of cardiovascular pathologies, with grave implications for worldwide health care systems. The metabolic syndrome is characterized by visceral obesity, insulin resistance, hypertension, chronic inflammation, and thrombotic disorders contributing to endothelial dysfunction and, subsequently, to accelerated atherosclerosis. Obesity is a key component in development of the metabolic syndrome and it is becoming increasingly clear that a central factor in this is the production by adipose cells of bioactive substances that directly influence insulin sensitivity and vascular injury. In this paper, we review advances in the understanding of biologically active molecules collectively referred to as “adipokines” and how dysregulated production of these factors in obese states mediates the pathogenesis of obesity associated metabolic syndrome.

Section snippets

Adiponectin

Adiponectin (also referred to as AdipQ, Acrp30, apMI) is expressed and secreted at very high levels in adipocytes.13 Until very recently, this protein was thought to be expressed exclusively in adipocytes43., 44., 45.; however, a few reports now suggest that low levels of adiponectin may also be expressed in other tissues.46., 47., 48. As a result of multimerization this protein is present in the circulation in various molecular weight forms including trimer, hexamer, and a number of high

Leptin

The discovery of leptin by Zhang et al in 199479 resulted in the appreciation of adipose tissue as more than just an inert storage depot for triglyceride. This factor is regarded as the prototypical adipokine, with secretion being regulated by the size of fat stores both in physiologic and pathophysiologic states.80., 81. Leptin is secreted almost exclusively by adipocytes as a 16 kDa product of the ob gene79 and signals via a family of plasma membrane receptors.82., 83. Leptin receptors are

Visfatin

Visfatin (pre-B cell colony-enhancing factor) is a newly identified adipokine that is highly enriched in visceral fat of both humans and mice, and the levels of this 52 kDa secreted protein increase during development of obesity.13., 110. Serum levels of visfatin are positively correlated with degree of visceral adiposity.13 This adipokine exerts insulin-mimetic effects on various tissues including liver, muscle, and fat.111., 112. A recent study reported differential regulation of visfatin

Glucocorticoids

Glucocorticoids play a pivotal role in regulation of fat metabolism, function, and distribution.113 The metabolic syndrome, which includes central obesity, insulin resistance, type 2 diabetes, and dyslipidemia resembles Cushing syndrome; however, unlike this syndrome, the levels of circulating glucocorticoid are not elevated in more common forms of obesity.114 This correlation was intriguing but until recently the role of glucocorticoids in prevalent forms of human obesity was not understood.113

Free Fatty Acids

Plasma levels of free (or non-esterified) fatty acids (FFAs) are elevated in obese individuals, with the major source being visceral adipose tissue.118., 119., 120. The concentrations of FFAs are mainly regulated by catecholamines (favoring lipolysis) and insulin (favoring lipogenesis) and as adipose tissue lipolysis is a major source of FFAs (particularly in obesity), these molecules are regarded as adipokines. Studies in the perfused pancreas demonstrate an involvement of FFAs in insulin

Inflammatory Mediators

Obesity is recognized as a state of low-grade inflammation,13 and recently features of acute-phase activation and low-grade inflammation, including elevated levels of fibrinogen, CRP, and IL-6, have been particularly associated with central or visceral obesity.41 This inflammatory state is a predominant feature in the metabolic syndrome and appears to be linked to vasculopathies and development of diabetes.132 In fact, the chronic inflammation present in obesity has been suggested as a

Tumor Necrosis Factor-Alpha

TNF-α is a proinflammatory adipokine that plays a primary role in stimulating expression of other inflammatory mediators including leptin and IL-6136., 137., 138., 139. whereas expression and secretion of antiinflammatory adiponectin is reduced in response to TNF-α.140., 141. It has been suggested that increased expression of TNF-α in obesity and subsequent reduced expression of adiponectin plays a significant role in development of the metabolic syndrome.142 Expression levels of TNF are

Interleukin-6

Interleukin-6 is a 26 kDa protein that functions as an immune-modulating cytokine.154 IL-6 is expressed in adipose tissue and also in hypothalamic nuclei involved in regulation of body composition.155 Adipose tissue contributes a significant proportion of total circulating IL-6,156., 157. with more of this adipokine being released from visceral adipose tissue compared with abdominal subcutaneous tissue.158 The role of IL-6 in the development of obesity and vascular pathology is ambiguous. Some

Plasminogen-Activator Inhibitor 1

Plasminogen-activator inhibitor 1 is a regulatory protein of the coagulation cascade, and elevated levels in inflammatory and obese states are a known risk factor for thrombosis.169 PAI-1 is a serine-protease inhibitor which acts to prevent generation of plasmin thus preventing extracellular matrix degradation and fibrinolysis.13 This decreased fibrinolysis coupled with obesity-induced increases in clotting factors and platelet activation underpin the development of a hypercoagulable state,

Angiotensinogen

Angiotensinogen along with all components of the renin-angiotensin system (RAS), including renin, angiotensin converting enzyme, angiotensin II, and AT-1 and AT-2 receptors, are expressed and secreted from adipose tissue, predominantly visceral depots.34., 176., 177. Several studies have shown that expression and activity of the RAS in adipose tissue, together with plasma levels of angiotensin, are all positively correlated with body fat mass.178., 179., 180. The RAS, with its effects on fluid

Conclusions

Over the past few years, a growing number of adipose-derived factors have been described, and many of these have been implicated in the association between central adiposity, cardiovascular pathology, and comorbidities including systemic inflammation, dyslipidemia, and type 2 diabetes. It is clear that the dysregulated expression and secretion of these adipokines, which occurs in obesity, underpin the vasculopathies and metabolic abnormalities characterizing the metabolic syndrome.

References (186)

  • K. Maeda et al.

    cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1)

    Biochem Biophys Res Commun

    (1996)
  • H.S. Berner et al.

    Adiponectin and its receptors are expressed in bone-forming cells

    Bone

    (2004)
  • A.R. Nawrocki et al.

    The delicate balance between fat and muscle: adipokines in metabolic disease and musculoskeletal inflammation

    Curr Opin Pharmacol

    (2004)
  • U.B. Pajvani et al.

    Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin: implications fpr metabolic regulation and bioactivity

    J Biol Chem

    (2003)
  • Y. Wang et al.

    Hydroxylation and glycosylation of the four conserved lysine residues in the collagenous domain of adiponectin: potential role in the modulation of its insulin-sensitizing activity

    J Biol Chem

    (2002)
  • A. Xu et al.

    Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes

    J Biol Chem

    (2005)
  • R. Shibata et al.

    Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of AMP-activated protein kinase signaling

    J Biol Chem

    (2004)
  • H. Waki et al.

    Impaired multimerization of human adiponectin mutants associated with diabetes: molecular structure and multimer formation of adiponectin

    J Biol Chem

    (2003)
  • T.S. Tsao et al.

    Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity: different oligomers activate different signal transduction pathways

    J Biol Chem

    (2003)
  • Y. Wang et al.

    Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner

    J Biol Chem

    (2005)
  • R.S. Ahima et al.

    Adipose tissue as an endocrine organ

    Trends Endocrinol Metab

    (2000)
  • L.A. Tartaglia et al.

    Identification and expression cloning of a leptin receptor, OB-R

    Cell

    (1995)
  • L.A. Tartaglia

    The leptin receptor

    J Biol Chem

    (1997)
  • R.B. Lynn et al.

    Autoradiographic localization of leptin binding in the choroid plexus of ob/ob and db/db mice

    Biochem Biophys Res Commun

    (1996)
  • D.W. White et al.

    Leptin receptor (OB-R) signaling: cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization

    J Biol Chem

    (1997)
  • Y. Wang et al.

    Leptin receptor action in hepatic cells

    J Biol Chem

    (1997)
  • C. Serradeil-Le Gal et al.

    Characterization and localization of leptin receptors in the rat kidney

    FEBS Lett.

    (1997)
  • N. Hoggard et al.

    Localization of leptin receptor mRNA splice variants in murine peripheral tissues by RT-PCR and in situ hybridization

    Biochem Biophys Res Commun

    (1997)
  • M.P. Lostao et al.

    Presence of leptin receptors in rat small intestine and leptin effect on sugar absorption

    FEBS Lett

    (1998)
  • M.Y. Wang et al.

    A novel leptin receptor isoform in rat

    FEBS Lett

    (1996)
  • T.J. Kieffer et al.

    Leptin receptors expressed on pancreatic beta-cells

    Biochem Biophys Res Commun

    (1996)
  • C. Bjorbaek et al.

    Identification of SOCS-3 as a potential mediator of central leptin resistance

    Mol Cell

    (1998)
  • G.M. Reaven

    Banting lecture 1988. Role of insulin resistance in human disease

    Diabetes

    (1988)
  • G.M. Reaven

    The metabolic syndrome: requiescat in pace

    Clin Chem

    (2005)
  • O. Pinhas-Hamie et al.

    Increased incidence of non-insulin-dependent diabetes mellitus among adolescents

    J Pediatr.

    (1996)
  • R. Sinha et al.

    Prevalence of impaired glucose tolerance among children and adolescents with marked obesity

    N Engl J Med

    (2002)
  • S.R. Daniels et al.

    Overweight in children and adolescents: pathophysiology, consequences, prevention, and treatment

    Circulation

    (2005)
  • S. Furukawa et al.

    Increased oxidative stress in obesity and its impact on metabolic syndrome

    J Clin Invest

    (2004)
  • C.T. Montague et al.

    The perils of portliness: causes and consequences of visceral adiposity

    Diabetes

    (2000)
  • Y. Matsuzawa et al.

    Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances

    Ann N Y Acad Sci

    (1999)
  • B.B. Kahn et al.

    Obesity and insulin resistance

    J Clin Invest

    (2000)
  • D.E. Moller et al.

    Metabolic syndrome: a clinical and molecular perspective

    Annu Rev Med

    (2005)
  • H. Masuzaki et al.

    A transgenic model of visceral obesity and the metabolic syndrome

    Science

    (2001)
  • Y. Matsuzawa et al.

    Adiponectin and metabolic syndrome

    Arterioscler Thromb Vasc Biol

    (2004)
  • C.J. Lyon et al.

    Minireview: adiposity inflammation and atherogenesis

    Endocrinology

    (2003)
  • P. Maison et al.

    Do different dimensions of the metabolic syndrome change together over time? Evidence supporting obesity as the central feature

    Diabetes Care

    (2001)
  • C. Lacquemant et al.

    Adipocytokins, obesity and development of type 2 diabetes

    [French] Med Sci (Paris)

    (2003)
  • B.E. Wisse

    The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity

    J Am Soc Nephrol

    (2004)
  • O. Hamdy

    Lifestyle modification and endothelial function in obese subjects

    Expert Rev Cardiovasc Ther

    (2005)
  • K.R. Rabin et al.

    Adiponectin: linking the metabolic syndrome to its cardiovascular consequences

    Expert Rev Cardiovasc Ther

    (2005)
  • Cited by (0)

    View full text