TGR5 contributes to ursodeoxycholic acid (UDCA)-mediated improvements in glucose regulation in mice

Bile acids (BAs) are amphipathic steroid derivatives, whose primary action is the solubilization of dietary lipids. However, BAs also play a critical role in glucose regulation. Numerous subtypes of BAs exist and they exhibit wide variation in their impact on glucose regulation. In particular, the BA subtype UDCA improves insulin sensitivity by decreasing endoplasmic reticulum (ER) stress and thus has been described as a “chemical chaperone.” The mechanism by which UDCA decreases ER stress and improves insulin sensitivity remains undefined. BAs signaling through Farnesoid X receptor (FXR) and TGR5 has been shown to improve glucose homeostasis. However, UDCA is an agonist for TGR5, but not FXR. TGR5 is a transmembrane G-protein coupled receptor with potent glucoregulatory benefits. Furthermore, as a hydrophilic BA subtype, UDCA is more likely to signal through a membrane-bound receptor than a nuclear receptor. Therefore, we tested the hypothesis that TGR5 contributes to the glucoregulatory benefits of UDCA supplementation. Tgr5+/+ (WT) and Tgr5-/- (KO) mice received high fat diet (HFD) with (WT UDCA, KO UDCA) and without (WT CON, KO CON) UDCA supplementation (n=8-10 per group). UDCA-treated mice received UDCA mixed in the diet such that animals consumed 150 mg/kg/d UDCA. Body weight, food intake and adiposity did not differ between groups. During and oral glucose tolerance test (OGTT), UDCA improved glucose tolerance in Tgr5+/+ but not in Tgr5-/- mice (Glucose AUC (mg/dl x 120 min): WT CON = 38991±2080, WT UDCA = 33961±917, KO CON = 34394±954, KO UDCA = 36759±2800; P<0.05 WT CON vs WT UDCA). Insulin and glucagon-like peptide-1 (GLP-1) secretion did not differ between groups. Together, our data show that TGR5 contributes to the glucoregulatory benefits of UDCA treatment, independently of GLP-1.