TGR5, bile acids and the metabolic syndrome.

Abstract

Low‐grade chronic inflammation, obesity and insulin resistance are all risk factors intimately linked with the metabolic syndrome. Interestingly, many of the signaling pathways that control inflammatory responses also intersect with those that control nutrient metabolism. Earlier work from our laboratory has demonstrated that BAs, through TGR5 activation, can exert systemic metabolic effects by promoting energy expenditure and GLP‐1 secretion, thereby preventing obesity and insulin resistance during high fat diet feeding. Activation of TGR5 signaling also suppresses pro‐inflammatory cytokine production in macrophages via a mechanism that involves inhibition of NFkB nuclear translocation and attenuates the development of atherosclerosis in LDLR−/− mice. More recently, we investigated the properties of macrophage TGR5 in the context of diabesity. We demonstrate that diet‐induced obese Tgr5−/− mice develop severe insulin resistance and exhibit increased adipose tissue and liver inflammation as a result of increased macrophage migration. These results underscore the importance of an intact TGR5 signaling pathway in macrophages to prevent and combat chronic inflammatory diseases, such as atherosclerosis and diabesity.