The role of adipose tissue M1/M2 macrophages in type 2 diabetes mellitus

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 obesity-induced chronic inflammation. Control of M1/M2 ATM polarity is a potential therapeutic target for the treatment of insulin resistance associated with obesity.