Elsevier

Immunology Letters

Volume 112, Issue 2, 15 October 2007, Pages 61-67
Immunology Letters

Review
Adipose tissue macrophages

https://doi.org/10.1016/j.imlet.2007.07.003Get rights and content

Abstract

It is now broadly accepted that low-grade chronic inflammation associated with obesity leads to the onset of insulin resistance and type 2 diabetes mellitus. Obesity-associated inflammation is characterized by an increased abundance of macrophages in adipose tissue along with production of inflammatory cytokines. Adipose tissue macrophages (ATMs) are suspected to be the major source of inflammatory mediators such as TNF-α and IL-6 that interfere with adipocyte function by inhibiting insulin action. However, ATMs phenotypically resemble alternatively activated (M2) macrophages and are capable of anti-inflammatory mediator production challenging the concept that ATMs are simply the “bad guys” in obese adipose tissue. Triggers promoting ATM recruitment, ATM functions and dysfunctions, and stimuli and molecular mechanisms that drive them into becoming detrimental to their environment are subject to current research. Strategies to interfere with ATM recruitment and adverse activation could give rise to novel options for treatment and prevention of insulin resistance and type 2 diabetes mellitus.

Introduction

Obesity is associated with a chronic low-grade inflammation that predisposes to insulin resistance and development of type 2 diabetes. These chronic inflammatory alterations are associated with increased abundance of macrophages in adipose tissue (AT). AT macrophages (ATMs) probably interfere with adipocyte function, which is an important factor for systemic insulin sensitivity. Thus, ATMs appear to critically contribute to the pathogenesis of type 2 diabetes mellitus and the metabolic syndrome, an umbrella term to encompass visceral obesity, hypertension, and impaired glucose and lipid metabolism conferring risk for cardiovascular disease. Recent studies have shed light on the phenotype of human and murine ATMs. However, many molecular details underlying the recruitment of macrophages to adipose tissue and the insulin desensitizing effects of ATMs are unresolved yet. This review recapitulates the current developments in these topics. Moreover, we summarize the progress on attempts to treat insulin resistance and hence prevent type 2 diabetes by interference with ATM recruitment and activation.

Section snippets

Obesity-induced chronic inflammation

Type 2 diabetes mellitus is currently one of the main health threats for humans due to the demographic increase of overweight or obese individuals and is causing enormous social an economical burdens [1]. Obesity, particularly visceral obesity that correlates with waist circumference, is one of the major risk factors to develop insulin resistance. Insulin resistance, i.e. reduced sensitivity to insulin action, is a fundamental step towards type 2 diabetes mellitus [2]. Importantly, obesity and

The M1/M2 concept of macrophage classification

Mirroring the Th1/Th2 concept of T-cell activation, a concept of M1/M2 polarization has recently been developed for macrophages. Depending on the stimuli such as cytokines and microbial products, macrophages develop into specialized cell types and exert unique functional properties [34]. Macrophages are classically stimulated by IFNγ alone or in combination with lipopolysaccharide (LPS), produce inflammatory cytokines (e.g., IL-1, IL-6, TNF-α), reactive oxygen species such as NO by iNOS

Targeting recruitment and activation of ATMs

As discussed above, genetic depletion of Mcp-1 and its receptor has improved metabolic parameters after high-fat diet feeding in several even though not all animal studies [28], [29], [33]. Hence, targeting Mcp-1 or Ccr-2 has been suggested for treatment of obesity-induced insulin resistance but this concept has to be proven in human obesity.

More progress has been made in elucidating the importance of distinct inflammatory signaling pathways for macrophage activation in AT inflammation.

Conclusions/outlook

ATMs are a peculiar type of macrophages that resembles the M2 type, but they also have the potential to act pro-inflammatory and thus detrimental to adipocyte function and insulin sensitivity. Despite the extensive evidence obtained from rodent studies, the hypothesis that ATMs significantly contribute to systemic insulin resistance has not yet been confirmed in humans. Still open questions on ATM biology include triggers inducing ATM recruitment and stimuli altering ATM function and

Acknowledgement

This work was supported by the Austrian Science Fund (P18776-B11 to T.M.S.).

References (95)

  • E.P. McGreal et al.

    Ligand recognition by antigen-presenting cell C-type lectin receptors

    Curr Opin Immunol

    (2005)
  • A. Mantovani et al.

    Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes

    Trends Immunol

    (2002)
  • J.Y. Lee et al.

    The modulation of inflammatory gene expression by lipids: mediation through Toll-like receptors

    Mol Cells

    (2006)
  • P.S. Laine et al.

    Palmitic acid induces IP-10 expression in human macrophages via NF-κB activation

    Biochem Biophys Res Commun

    (2007)
  • M.J. Song et al.

    Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes

    Biochem Biophys Res Commun

    (2006)
  • P. Zimmet et al.

    Global and societal implications of the diabetes epidemic

    Nature

    (2001)
  • J.P. Despres et al.

    Abdominal obesity and metabolic syndrome

    Nature

    (2006)
  • S.E. Kahn et al.

    Obesity is a major determinant of the association of C-reactive protein levels and the metabolic syndrome in type 2 diabetes

    Diabetes

    (2006)
  • C.S. Kim et al.

    Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters

    Int J Obes (Lond)

    (2006)
  • G.S. Hotamisligil et al.

    Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance

    Science

    (1993)
  • R.C. Moraes et al.

    Study of the alteration of gene expression in adipose tissue of diet-induced obese mice by microarray and reverse transcription-polymerase chain reaction analyses

    Endocrinology

    (2003)
  • H. Xu et al.

    Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance

    J Clin Invest

    (2003)
  • S.P. Weisberg et al.

    Obesity is associated with macrophage accumulation in adipose tissue

    J Clin Invest

    (2003)
  • K. Clement et al.

    Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects

    FASEB J

    (2004)
  • N. Stefan et al.

    Adiponectin—its role in metabolism and beyond

    Horm Metab Res

    (2002)
  • P. Trayhurn

    Adipocyte biology

    Obes Rev

    (2007)
  • T. Suganami et al.

    A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor α

    Arterioscler Thromb Vasc Biol

    (2005)
  • C.N. Lumeng et al.

    Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins

    Am J Physiol Endocrinol Metab

    (2007)
  • J. Jager et al.

    Interleukin-1β-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression

    Endocrinology

    (2007)
  • D. Lacasa et al.

    Macrophage-secreted factors impair human adipogenesis: involvement of proinflammatory state in preadipocytes

    Endocrinology

    (2007)
  • B.B. Kahn et al.

    Obesity and insulin resistance

    J Clin Invest

    (2000)
  • R. Cancello et al.

    Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss

    Diabetes

    (2005)
  • R. Cancello et al.

    Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity

    Diabetes

    (2006)
  • C.A. Curat et al.

    Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin

    Diabetologia

    (2006)
  • M. Zeyda et al.

    Human adipose tissue macrophages are of an anti inflammatory phenotype but capable of excessive pro inflammatory mediator production

    Int J Obes

    (2007)
  • I. Harman-Boehm et al.

    Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the co-morbidities of obesity

    J Clin Endocrinol Metab

    (2007)
  • K.E. Wellen et al.

    Inflammation, stress, and diabetes

    J Clin Invest

    (2005)
  • H. Wu et al.

    T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity

    Circulation

    (2007)
  • H. Kanda et al.

    MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity

    J Clin Invest

    (2006)
  • S.P. Weisberg et al.

    CCR2 modulates inflammatory and metabolic effects of high-fat feeding

    J Clin Invest

    (2006)
  • C.N. Lumeng et al.

    Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity

    Diabetes

    (2007)
  • F.Y. Chow et al.

    Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice

    Diabetologia

    (2007)
  • Inouye KE, Shi H, Howard JK, Daly CH, Lord GM, Rollins BJ, et al. Absence of CC chemokine ligand 2 does not limit...
  • S. Gordon

    Alternative activation of macrophages

    Nat Rev Immunol

    (2003)
  • C.F. Anderson et al.

    Modulating macrophage function with IgG immune complexes

    J Endotoxin Res

    (2002)
  • H. Takahashi et al.

    Influence of systemic inflammatory response syndrome on host resistance against bacterial infections

    Crit Care Med

    (2004)
  • P. Loke et al.

    Alternatively activated macrophages induced by nematode infection inhibit proliferation via cell-to-cell contact

    Eur J Immunol

    (2000)
  • Cited by (0)

    View full text