Elsevier

Physiology & Behavior

Volume 94, Issue 2, 23 May 2008, Pages 206-218
Physiology & Behavior

The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance

https://doi.org/10.1016/j.physbeh.2007.10.010Get rights and content

Abstract

Research of the past decade has increased our understanding of the role adipose tissue plays in health and disease. Adipose tissue is now recognized as a highly active metabolic and endocrine organ. Adipocytes are of importance in buffering the daily influx of dietary fat and exert autocrine, paracrine and/or endocrine effects by secreting a variety of adipokines. The normal function of adipose tissue is disturbed in obesity, and there is accumulating evidence to suggest that adipose tissue dysfunction plays a prominent role in the development and/or progression of insulin resistance. Obese individuals often have enlarged adipocytes with a reduced buffering capacity for lipid storage, thereby exposing other tissues to an excessive influx of lipids, leading to ectopic fat deposition and insulin resistance in situations where energy intake exceeds energy expenditure. In addition, adipose tissue blood flow is decreased in obesity. This impairment may affect lipid handling in adipose tissue and, thereby, further contribute to excessive fat storage in non-adipose tissues. On the other hand, adipose tissue hypoperfusion may induce hypoxia in this tissue. Adipose tissue hypoxia may result in disturbances in adipokine secretion and increased macrophage infiltration in adipose tissue, events that are frequently observed in obesity. In this review, it is discussed how enlarged adipocytes, an impaired blood flow through adipose tissue, adipose tissue hypoxia, adipose tissue inflammation and macrophage infiltration are interrelated and may induce insulin resistance.

Introduction

The prevalence of obesity has reached epidemic proportions globally, with more than 1 billion adults being overweight, of whom at least 300 million are obese [1]. This poses a major public health issue, since obesity is a major contributor to the global burden of chronic diseases. Abdominal obesity plays a central role in the metabolic syndrome and is a major risk factor for chronic diseases, such as type 2 diabetes mellitus and cardiovascular disease [2]. Not surprisingly, the prevalence of obesity-related disorders is also increasing at an alarming rate. In fact, obesity is the most important risk factor for the development of type 2 diabetes [3], which is further stressed by the fact that obesity, body fat distribution and weight gain throughout adulthood are important predictors of diabetes [3], [4]. Furthermore, adiposity is associated with insulin resistance even over relatively normal ranges of body fatness. Although the relationship between obesity, insulin resistance and cardiovascular disease is well-recognized [5], the mechanisms involved remain relatively poorly understood.

Adipose tissue dysfunction plays a crucial role in the pathogenesis of obesity-related insulin resistance and type 2 diabetes, as has recently been reviewed [6], [7], [8]. The aim of this review is to discuss the evidence that enlarged adipocytes, an impaired adipose tissue blood flow (ATBF), adipose tissue hypoxia, local inflammation in adipose tissue and adipose tissue macrophage infiltration seem to be interrelated and may lead to disturbances in adipokine secretion, lipid overflow, and excessive fat storage in non-adipose tissues, which together may result in the development and/or progression of insulin resistance.

Section snippets

Adipose tissue as lipid storage depot

Obesity is the result of an imbalance between energy intake and energy expenditure. When energy intake exceeds energy expenditure the energy surplus is stored in various organs. Adipose tissue is the main lipid storage depot in our body, and is of crucial importance in buffering the daily influx of dietary fat entering the circulation. Adipose tissue exerts its buffering action by suppressing the release of non-esterified fatty acids into the circulation and by increasing the clearance of

Importance of adipose tissue blood flow in lipid metabolism

Tissue-specific regulation of blood flow is required to meet local metabolic and physiological demands under varying conditions. Blood flow may be an important regulator of metabolism in both muscle [27] and adipose tissue [28], [29], [30]. There is evidence that disturbances in adipose tissue blood flow (ATBF) may affect adipose tissue lipid handling, thereby contributing to an increased lipid supply to non-adipose tissues, which in turn may lead to ectopic fat deposition as discussed above.

Link between adipocyte size and insulin resistance

Enlargement of adipocytes is frequently observed in obesity and has also been demonstrated in pre-diabetic individuals and in type 2 diabetics [48], [49], [50]. The increased adipocyte size may represent a failure in the recruitment of new adipocytes due to impaired differentiation, which may have a genetic origin [51]. An impaired adipocyte differentiation appears to be a precipitating factor in the development of type 2 diabetes [49], [50]. In accordance with this, it has recently been shown

Adipose tissue as an endocrine organ

Until recently, adipose tissue was seen as a passive organ for energy storage. Research of the past decade has shown the complex nature of adipose tissue and clearly demonstrated that the traditional view of adipose tissue is no longer valid. Adipocytes are now known to express and secrete a variety of adipokines, which may act at both the local (autocrine and/or paracrine) and systemic (endocrine) level. These factors among others include cytokines, growth factors, adiponectin, resistin,

Importance of inflammation in insulin resistance

Studies in the past decade left little doubt that inflammatory pathways are critical in the mechanisms underlying insulin resistance and type 2 diabetes, at least in cultured cells and animal models [112], [113], [114], [115], [116]. Accumulating evidence suggests that this may also be the case in humans. Much progress has been made in identifying mechanisms by which the inflammatory response may cause insulin resistance. Dysregulation of adipokine production and/or secretion may both have

Adipose tissue inflammation and macrophage infiltration

Adipose tissue is a heterogeneous tissue containing different cell types, including mature adipocytes, pre-adipocytes, endothelial cells, vascular smooth muscle cells, leukocytes, monocytes and macrophages. Due to this heterogeneity, several studies have been performed to establish the cellular origin of the adipokines that are expressed in adipose tissue. Macrophages are now recognized as important non-adipocyte cells that contribute to adipose tissue production of inflammatory factors. In

Role for adipose tissue hypoxia in insulin resistance?

Epidemiological and clinical studies have shown that obstructive sleep apnea (OSA) may contribute to the development of insulin resistance [164], [165], [166], possibly via cycles of intermittent hypoxia resulting from periodic collapse of the upper airway during sleep. Epidemiological studies have revealed an association between the degree of hypoxia and insulin resistance [164], [165], [166]. Interestingly, intermittent hypoxia causes acute insulin resistance in mice due to decreased skeletal

Summary and perspectives

Abdominal obesity is strongly associated with insulin resistance and the development of type 2 diabetes and cardiovascular disease. Enormous progress has been made over the past few years in the attempt to understand the mechanisms underlying obesity-related insulin resistance. It is now well-recognized that adipose tissue is a highly active metabolic and endocrine organ. Adipocytes are of crucial importance in buffering the daily influx of dietary fat and exert autocrine, paracrine and/or

References (203)

  • Y. Arita et al.

    Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity

    Biochem Biophys Res Commun

    (1999)
  • World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World...
  • G.M. Reaven

    Banting lecture 1988. Role of insulin resistance in human disease

    Diabetes

    (1988)
  • J.M. Chan et al.

    Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men

    Diabetes Care

    (1994)
  • T.S. Han et al.

    Associations of body composition with type 2 diabetes mellitus

    Diabet Med

    (1998)
  • S.M. Grundy et al.

    Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition

    Circulation

    (2004)
  • M. Qatanani et al.

    Mechanisms of obesity-associated insulin resistance: many choices on the menu

    Genes Dev

    (2007)
  • D.B. Savage et al.

    Disordered lipid metabolism and the pathogenesis of insulin resistance

    Physiol Rev

    (2007)
  • S.E. Shoelson et al.

    Inflammation and insulin resistance

    J Clin Invest

    (2006)
  • K.N. Frayn

    Adipose tissue and the insulin resistance syndrome

    Proc Nutr Soc

    (2001)
  • N.G. Forouhi et al.

    Relation of triglyceride stores in skeletal muscle cells to central obesity and insulin sensitivity in European and South Asian men

    Diabetologia

    (1999)
  • S. Jacob et al.

    Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects

    Diabetes

    (1999)
  • D.A. Pan et al.

    Skeletal muscle triglyceride levels are inversely related to insulin action

    Diabetes

    (1997)
  • K. Koyama et al.

    Tissue triglycerides, insulin resistance, and insulin production: implications for hyperinsulinemia of obesity

    Am J Physiol

    (1997)
  • M.A. Banerji et al.

    Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM

    Int J Obes Relat Metab Disord

    (1995)
  • P. Bjorntorp

    Liver triglycerides and metabolism

    Int J Obes Relat Metab Disord

    (1995)
  • C. Fanelli et al.

    Demonstration of a critical role for free fatty acids in mediating counterregulatory stimulation of gluconeogenesis and suppression of glucose utilization in humans

    J Clin Invest

    (1993)
  • E. Ferrannini et al.

    Effect of fatty acids on glucose production and utilization in man

    J Clin Invest

    (1983)
  • G.F. Lewis et al.

    Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans

    Diabetes

    (1997)
  • C.D. Byrne et al.

    Interaction of non-esterified fatty acid and insulin in control of triacylglycerol secretion by Hep G2 cells

    Biochem J

    (1991)
  • M.M. Hennes et al.

    Effects of free fatty acids and glucose on splanchnic insulin dynamics

    Diabetes

    (1997)
  • J. Svedberg et al.

    Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes

    Diabetes

    (1990)
  • S.R. Wiesenthal et al.

    Free fatty acids impair hepatic insulin extraction in vivo

    Diabetes

    (1999)
  • K.N. Frayn et al.

    Are increased plasma non-esterified fatty acid concentrations a risk marker for coronary heart disease and other chronic diseases?

    Clin Sci (Lond)

    (1996)
  • O.P. Ganda

    Lipoatrophy, lipodystrophy, and insulin resistance

    Ann Intern Med

    (2000)
  • O. Gavrilova et al.

    Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice

    J Clin Invest

    (2000)
  • A.D. Baron et al.

    Role of blood flow in the regulation of muscle glucose uptake

    Annu Rev Nutr

    (1997)
  • J. Bulow et al.

    Influence of blood flow on fatty acid mobilization form lipolytically active adipose tissue

    Pflugers Arch

    (1981)
  • J. Galitzky et al.

    Role of vascular alpha-2 adrenoceptors in regulating lipid mobilization from human adipose tissue

    J Clin Invest

    (1993)
  • J.S. Samra et al.

    Effects of epinephrine infusion on adipose tissue: interactions between blood flow and lipid metabolism

    Am J Physiol

    (1996)
  • J.L. Ardilouze et al.

    Nitric oxide and beta-adrenergic stimulation are major regulators of preprandial and postprandial subcutaneous adipose tissue blood flow in humans

    Circulation

    (2004)
  • J.L. Ardilouze et al.

    Subcutaneous adipose tissue blood flow varies between superior and inferior levels of the anterior abdominal wall

    Int J Obes Relat Metab Disord

    (2004)
  • J. Bulow et al.

    Blood flow in skin, subcutaneous adipose tissue and skeletal muscle in the forearm of normal man during an oral glucose load

    Acta Physiol Scand

    (1987)
  • K. Evans et al.

    Effects of an oral and intravenous fat load on adipose tissue and forearm lipid metabolism

    Am J Physiol

    (1999)
  • G.H. Goossens et al.

    Angiotensin II: a major regulator of subcutaneous adipose tissue blood flow in humans

    J Physiol

    (2006)
  • K.N. Frayn et al.

    Integrative physiology of human adipose tissue

    Int J Obes Relat Metab Disord

    (2003)
  • G.H. Goossens et al.

    Endocrine role of the renin–angiotensin system in human adipose tissue and muscle: effect of beta-adrenergic stimulation

    Hypertension

    (2007)
  • P.A. Jansson et al.

    Relationship between blood pressure, metabolic variables and blood flow in obese subjects with or without non-insulin-dependent diabetes mellitus

    Eur J Clin Invest

    (1998)
  • L.K. Summers et al.

    Subcutaneous abdominal adipose tissue blood flow: variation within and between subjects and relationship to obesity

    Clin Sci (Lond)

    (1996)
  • K.A. Virtanen et al.

    Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans

    J Clin Endocrinol Metab

    (2002)
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