ReviewAdipose tissue macrophages
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.).
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