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Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-α

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Abstract

Insulin resistance is a fundamental defect that precedes the development of the full insulin resistance syndrome as well as β cell failure and type 2 diabetes. Tumor necrosis factor-α (TNF-α), a paracrine/autocrine factor highly expressed in adipose tissues of obese animals and human subjects, is implicated in the induction of insulin resistance seen in obesity and type 2 diabetes. Here, we review several molecular aspects of adipose tissue physiology, and highlight the direct effects of TNF-α on the functions of adipose tissue including induction of lipolysis, inhibition of insulin signaling, and alterations in expression of adipocyte important genes through activation of NF-κB, as well as their pertinence to insulin sensitivity of adipocytes. We also review the ability of TNF-α to inhibit synthesis of several adipocyte-specific proteins including Acrp30 (adiponectin) and enhance release of free fatty acids (FFAs) from adipose tissue, and discuss how these factors may act as systemic mediators of TNF-α and affect whole body energy homeostasis and overall insulin sensitivity. On the basis of these mechanisms, we examine the therapeutic potential of blocking specific autocrine/paracrine signaling pathways in adipocytes, particularly those involving NF-κB, in the treatment of type 2 diabetes.

Introduction

Type 2 diabetes is characterized in part by elevated plasma levels of free fatty acids (FFAs) and glucose, and is associated with a cluster of abnormalities, such as central obesity, dyslipidemia, hyperinsulinemia, elevated plasma inflammatory markers, diminished plasma Acrp30 (adiponectin) levels, impaired fibrinolysis, vascular abnormalities, and hypertension. This cluster of abnormalities, referred to as the metabolic or insulin resistance syndrome, is associated with increased risk for cardiovascular and cerebrovascular diseases [1], [2], [3], [4], [5], [6].

Clinicians as well as researchers in the diabetes field have long been puzzled by the fact that anti-diabetic medications aimed at lowering plasma glucose levels, such as correcting relative insulin deficiency, inhibiting hepatic glucose production, and delaying glucose absorption from the gastrointestinal tract, often fail to restore metabolic homeostasis and prevent the progression of the disease and its complications. In contrast, a new class of insulin-sensitizing compounds, the thiazolidinediones, enhances insulin sensitivity and restores metabolic homeostasis while improving the cluster of abnormalities that occur in type 2 diabetes [7], [8], [9], [10], [11]. This highlights the essential need for restoring overall insulin sensitivity in the clinical management of type 2 diabetes.

Insulin regulates systemic energy homeostasis by coordinating the storage, mobilization and utilization of FFA and glucose in adipose tissue, liver, and skeletal muscle. The development of insulin resistance in these major insulin-target tissues evokes major metabolic consequences, and is widely recognized as a fundamental defect that precedes the development of the full insulin resistance syndrome and subsequent β cell failure [1], [12]. Thus, understanding the regulation of insulin responsiveness in major insulin-target tissues and the molecular mechanisms driving the development of insulin resistance become especially important given the therapeutic potential of improving insulin sensitivity in treatment of type 2 diabetes and its associated complications, such as atherosclerosis.

Investigation of the defects in insulin signal transduction in major insulin-responsive tissues and its contribution to the development of systemic insulin resistance has been facilitated by mouse genetic studies using animal models with tissue-specific knock-outs of the insulin receptor and/or other components of the insulin signaling pathway, and by the identification of specific phenotypes associated with the loss of insulin signaling in each of the major insulin-target tissues as well as the compensatory effects in vivo [13], [14], [15], [16], [17], [18], [19], [20]. Insulin signal transduction and its pertinence to systemic insulin sensitivity has been the topic of a number of recent reviews [13], [14], [21], [22], [23], [24], [25].

In parallel, recent studies have also identified a variety of factors, independent of or co-existing with defects in insulin signal transduction, as contributing causes of insulin resistance seen in the clinical settings of obesity and obesity-linked type 2 diabetes. Notably, many of these factors, such as FFAs, tumor necrosis factor-α (TNF-α), leptin, interleukin-6 (IL-6), adipocyte complement-related protein of 30 kDa (Acrp30, adiponectin), and resistin, are secreted by adipose tissue. Current understanding of the biological and physiological circuitry controlling insulin sensitivity suggest that adipose tissue is indeed an integrator of endocrine, autocrine/paracrine, metabolic, and inflammatory signals. Adipose tissue modulates multiple processes including whole body metabolic homeostasis, immune and inflammatory response, blood coagulation, and reproduction. The secretory function of adipose tissue and its impact on multiple physiological processes in the context of normal and disease settings has been the subject of a recent general review [26]. Here, we examine recent progress on several adipocytederived factors and their functional involvement in whole body energy metabolism and overall insulin sensitivity, with a focus on the direct and indirect effects of adipose tissue-derived TNF-α.

Section snippets

Metabolic effects of insulin

Insulin plays a critical role in maintaining the homeostasis of energy metabolism and coordinates the storage and utilization of fuel molecules in adipose tissue, liver, and skeletal muscle. The postprandial rise in plasma insulin concentrations promotes glucose uptake and its conversion to glycogen and/or triglyceride by muscle and adipose tissue. In parallel, hepatic glucose production is strongly inhibited as a result of insulin-dependent suppression of gluconeogenesis and glycogenolysis, as

Metabolic consequences of insulin resistance

Insulin resistance refers to a state in which physiological concentrations of insulin produce a less than normal response. A major metabolic consequence of insulin resistance is hyperglycemia, resulting from the failure of insulin to suppress hepatic glucose production and to promote glucose uptake and metabolism by peripheral tissues. Pancreatic β cells respond to excess plasma glucose by secreting more insulin to overcome the effects of insulin resistance and to maintain normal plasma glucose

Role of adipose tissue in energy metabolism and overall insulin sensitivity

Adipose tissue is a major site of energy storage and an important determinant of overall insulin sensitivity. In the postprandial state, the increase in plasma insulin concentration promotes glucose uptake, glycogen synthesis, fatty acid synthesis and de novo triglyceride synthesis in adipocytes, while potently suppressing FFA release in part by inhibiting the activity of hormone-sensitive lipase. Insulin also activates lipoprotein lipase in adipose tissue and results in increased clearance of

Modulators of adipocyte function and overall insulin sensitivity

Adipose tissue itself is subject to coordinated regulation by multiple hormonal signals as well as signals from the sympathetic nervous system. Moreover, it is increasingly recognized that several adipose-derived endocrine and paracrine/autocrine mediators play an essential role in the regulation of adipocyte function, and especially sensitivity to insulin action. Indeed, altered levels of a number of adipose tissue-derived endocrine and autocrine/paracrine factors, such as leptin, TNF-α, and

Insulin resistance in adipose tissue: direct and indirect effects of TNF-α

Since 80% of the patients with type 2 diabetes are obese, and obesity with or without over hyperglycemia is associated with insulin resistance, extensive efforts have been devoted to identify the molecular mediator(s) that links obesity to insulin resistance. One attractive candidate for such a link is TNF-α, since the level of TNF-α mRNA and protein are elevated in adipose tissues of obese rodents and humans. Although many other factors may precipitate the development of insulin resistance in

Acknowledgements

This work was supported in part by National Institute of Health grant R37-DK-47618 to H.F.L. H.R. was supported by a postdoctoral fellowship from the American Diabetes Association and currently holds a Postdoctoral Fellowship for Physician Scientists from the Howard Hughes Medical Institute. We thank Professor Henry J. Pownall for his critical reading of this paper prior to its submission.

References (112)

  • M. Kriegler et al.

    A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF

    Cell

    (1988)
  • P. Randle et al.

    The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus

    Lancet

    (1963)
  • J.L. Dixon et al.

    Regulation of hepatic secretion of apolipoprotein Bcontaining lipoproteins: information obtained from cultured liver cells

    J. Lipid Res.

    (1993)
  • E.O. Balasse et al.

    Influence of nicotinic acid on the rates of turnover and oxidation of plasma glucose in man

    Metabolism

    (1973)
  • R.A. Igal et al.

    Mitochondrial glycerol phosphate acyltransferase directs the incorporation of exogenous fatty acids into triacylglycerol

    J. Biol. Chem.

    (2001)
  • P.E. Scherer et al.

    A novel serum protein similar to C1q, produced exclusively in adipocytes

    J. Biol. Chem.

    (1995)
  • 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)
  • E. Hu et al.

    AdipoQ is a novel adipose-specific gene dysregulated in obesity

    J. Biol. Chem.

    (1996)
  • A.H. Berg et al.

    ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism

    Trends Endocrinol. Metab.

    (2002)
  • Y. Arita et al.

    Paradoxical 33 decrease of an adipose-specific protein, adiponectin, in obesity

    Biochem. Biophys. Res. Commun.

    (1999)
  • P. Arner

    Insulin resistance in type 2 diabetes: role of fatty acids

    Diabetes Metab. Res. Rev.

    (2002)
  • H.E. Lebovitz

    Insulin resistance: definition and consequences

    Exp. Clin. Endocrinol. Diabetes

    (2001)
  • G.M. Reaven

    Role of insulin resistance in human disease (syndrome X): an expanded definition

    Annu. Rev. Med.

    (1993)
  • G.M. Reaven

    Pathophysiology of insulin resistance in human disease

    Physiol. Rev.

    (1995)
  • A.R. Saltiel et al.

    Thiazolidinediones in the treatment of insulin resistance and type II diabetes

    Diabetes

    (1996)
  • H.E. Lebovitz et al.

    Insulin resistance and its treatment by thiazolidinediones

    Recent Prog. Horm. Res.

    (2001)
  • M. Stumvoll et al.

    Glitazones: clinical effects and molecular mechanisms

    Ann. Med.

    (2002)
  • M. Stumvoll et al.

    Insulin resistance and insulin sensitizers

    Horm. Res.

    (2001)
  • R.A. DeFronzo et al.

    Pathogenesis of NIDDM. A balanced overview

    Diabetes Care

    (1992)
  • T. Kitamura et al.

    Insulin receptor knockout mice

    Annu. Rev. Physiol.

    (2003)
  • F. Mauvais-Jarvis et al.

    Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance

    Clin. Endocrinol. (Oxf.)

    (2002)
  • C. Guerra et al.

    Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance

    J. Clin. Invest.

    (2001)
  • J.C. Bruning et al.

    Role of brain insulin receptor in control of body weight and reproduction

    Science

    (2000)
  • G. Jiang et al.

    Pi 3-kinase and its up- and down-stream modulators as potential targets for the treatment of type II diabetes

    Front Biosci.

    (2002)
  • B.B. Kahn

    Lilly lecture 1995. Glucose transport: pivotal step in insulin action

    Diabetes

    (1996)
  • M.F. White

    IRS proteins and the common path to diabetes

    Am. J. Physiol. Endocrinol. Metab.

    (2002)
  • B.J. Goldstein

    Insulin resistance as the core defect in type 2 diabetes mellitus

    Am. J. Cardiol.

    (2002)
  • P. Trayhurn et al.

    Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ

    Proc. Nutr. Soc.

    (2001)
  • R.A. DeFronzo et al.

    Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus

    J. Clin. Invest.

    (1985)
  • B.C. Martin et al.

    Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study

    Lancet

    (1992)
  • S. Lillioja et al.

    Insulin resistance and insulin secretory dysfunction as 24 precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians

    N Engl. J. Med.

    (1993)
  • Y.T. Kruszynska et al.

    Fatty acid-induced insulin resistance: decreased muscle PI3K activation but unchanged Akt phosphorylation

    J. Clin. Endocrinol. Metab.

    (2002)
  • G. Boden et al.

    Mechanisms of fatty acid-induced inhibition of glucose uptake

    J. Clin. Invest

    (1994)
  • P. Staehr et al.

    Effects of free fatty acids per se on glucose production, gluconeogenesis, and glycogenolysis

    Diabetes

    (2003)
  • A. Laws

    Free fatty acids, insulin resistance and lipoprotein metabolism

    Curr. Opin. Lipidol.

    (1996)
  • M. Shimabukuro et al.

    Fatty acid-induced-β cell apoptosis: a link between obesity and diabetes

    Proc. Natl. Acad. Sci. U.S.A.

    (1998)
  • H. Ruan et al.

    Profiling gene transcription in vivo reveals adipose tissue as an immediate target of TNF-α: implications for insulin resistance

    Diabetes

    (2002)
  • E.A. Carswell et al.

    An endotoxininduced serum factor that causes necrosis of tumors

    Proc. Natl. Acad. Sci. U.S.A.

    (1975)
  • B. Beutler et al.

    Identity of tumour necrosis factor and the macrophage-secreted factor cachectin

    Nature

    (1985)
  • M. Kawakami et al.

    Lipoprotein lipase suppression in 3T3-L1 cells by an endotoxin-induced mediator from exudate cells

    Proc. Natl. Acad. Sci. U.S.A.

    (1982)
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