Figure 6.

Bile acid-activated TGR5 signaling. TGR5 is expressed in brown adipocytes, macrophages/monocytes and hepatic Kupffer cells, gallbladder epithelium, and intestine, with especially high levels in the colon. TGR5 is the first G protein-coupled receptor (GPCR) identified as a bile acid-activated membrane receptor. TGR5 is a Gαs GPCR activated by secondary bile acids, lithocholic acid (LCA) and TLCA to induce cAMP signaling through activation of adenylyl cyclase (AC). TGR5 signaling may increase insulin sensitivity through two mechanisms. (i) In brown adipose tissue, cAMP induces type 2 deiodinase (DIO2), which converts and activates thyroid hormone T₄ to T₃ to stimulate energy metabolism in mitochondria by activating oxidative phosphorylation (OXphor) and uncoupling protein-1 (UCP-1). (ii) In the intestine, cAMP stimulates glucagon like peptide-1 (GLP-1) in L cells, which stimulates insulin secretion in the pancreas. TGR5 also has anti-inflammatory functions by antagonizing of TNFα and NF-κB-dependent induction of proinflammatory cytokines in intestine and macrophages, thus, protecting against colitis, inflammatory bowel disease and Crohn’s disease, and also atherosclerosis.