Macrophage-mediated inflammation in metabolic disease

Abstract

Metabolism and immunity are two fundamental systems of metazoans. The presence of immune cells, such as macrophages, in metabolic tissues, suggests dynamic, on-going crosstalk between these two regulatory systems. Here, we discuss how changes in recruitment and activation of macrophages contribute to metabolic homeostasis. In particular, we focus our discussion on the pathogenic and protective functions of classically (M1) and alternatively (M2) activated macrophages, respectively, in experimental models of obesity and metabolic disease.

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

“…An infiltration of macrophages into these tissues is seen in animal models of obesity and diabetes as well as in obese human individuals with metabolic syndrome or T2DM. These cells are crucial for the production of pro-inflammatory cytokines [4], including TNFα, IL-6 and IL-1β. They act in an autocrine and paracrine manner to promote insulin resistance by interfering with insulin signaling in peripheral tissues through activation of the c-JUN N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) pathways [2].…”

“…More recently, adipose tissue has been associated with a marked accumulation of immune cells in its stromovascular fraction during obesity [4] (Figure 1). Particularly, obesity induces an infiltration of macrophages in adipose tissue of both mice and humans [30,31].…”

“…Moreover, weight loss induced by surgery [29] or diet and exercise [10] results in a reduction in the number of adipose tissue macrophages in parallel to the decreased expression of pro-inflammatory markers in both adipose tissue and plasma of obese individuals. M a n u s c r i p t 6 Macrophages can be classified into two distinct subtypes: the "classically activated macrophages" phenotype, termed M1, which secrete pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and the "alternatively activated macrophages" phenotype, termed M2 which produce anti-inflammatory cytokines such as IL-10 [4]. While well-established in mice [34,35], the existence of distinct M1 and M2 subsets of adipose tissue macrophages has not been confirmed in human, where macrophages have rather been described as being a mix between M1 and M2 phenotypes [36].…”

“…In addition to adipose tissue macrophages infiltration, obesity causes a phenotypic switch from the M2 to M1 phenotype, correlating with insulin resistance both in mice and humans [34][35][36]. Direct and paracrine signals issued from M1 macrophages can impair insulin signaling and adipogenesis in adipocytes whereas M2 macrophages seem to protect against obesity-induced insulin resistance [4].…”

“…The progression from obesity-related insulin resistance to T2DM remains poorly understood but implicates a failure of pancreatic β-cells to compensate for insulin resistance leading to chronic hyperglycaemia. A chronic low-grade inflammation and an activation of the immune system are observed in abdominal obesity and may have a role in the pathogenesis of obesity-related metabolic disorders [2][3][4][5]. This review summarizes data implicating the immune system in the pathophysiogy of insulin resistance and T2DM.…”