The role of adipose tissue M1/M2 macrophages in type 2 diabetes mellitus
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REVIEW ARTICLE
The role of adipose tissue M1/M2 macrophages in type 2 diabetes mellitus Shiho Fujisaka1 Received: 30 November 2020 / Accepted: 1 December 2020 © The Japan Diabetes Society 2020
Abstract Obesity and insulin resistance are closely associated with a state of low-grade inflammation in the body, and adipose tissue macrophages (ATMs) play central roles in this inflammation. ATMs are known to exhibit marked functional heterogeneity. M1 ATMs produce inflammatory cytokines and induce insulin resistance. On the other hand, the majority of ATMs in lean individuals are M2 ATMs, which have anti-inflammatory potential. We found that M1 and M2 ATMs can be clearly distinguished using CD11c and CD206 as markers, and that both the number of the M1 and M2 ATMs and the M1/M2 ratio are correlated with the degree of insulin resistance. M1/M2 polarity in the adipose tissue is influenced not only by the level of secretion of various polarizing adipokines and chemokines, but also by factors in the local microenvironment, such as hypoxia. M1 ATMs acquire their polarity via activation of hypoxia-inducible factor-1α (HIF-1α) by local hypoxia, and absence of HIF-1α in the myeloid cells appears to enhance insulin sensitivity by promoting angiogenesis in adipose tissue. On the other hand, the resident M2 ATMs interact with adipose tissue progenitors to control adiposity. Thus, beyond their role as immunoregulatory cells, the M1/M2 ATMs also regulate the microenvironment in the adipose tissue and control insulin sensitivity. Recently, we have shown that interventions in the gut microbiota may be effective in controlling obesityinduced chronic inflammation. Control of M1/M2 ATM polarity is a potential therapeutic target for the treatment of insulin resistance associated with obesity. Keywords Insulin resistance · Macrophage · Inflammation · Obesity · Microbiota
Introduction Development of obesity-associated insulin resistance is promoted by systemic inflammation caused by increased levels of inflammatory cytokines, such as TNFα, IL-6, MCP-1, and IL-1β, and the major site of inflammation is the adipose tissue. Increased number of ATMs strongly contributes to its mechanisms [1, 2]. ATMs show highly heterogeneous characteristics, and include at least two major populations called the classically activated, or M1, ATMs and alternatively activated, or M2, ATMs [3]. Originally, the concept of M1 and M2 macrophages was derived from in vitro studies. M1 macrophages are mainly induced by Th1 signaling, involving factors such as lipopolysaccharide (LPS) and IFNγ, and * Shiho Fujisaka [email protected]‑toyama.ac.jp 1
express high levels of inflammatory cytokines. M2 macrophages, on the other hand, are induced by Th2 signaling, involving factors such as IL-4 and IL-13, and are associated with anti-inflammatory reactions. In healthy adipose tissue, more than 90% of the ATMs are of the M2 phenotype, which exhibit anti-inflammatory potential. As obesity progresses, Ly6c+ inflammatory monocytes recruited into the adipose tissue differentiate int
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