OR28-5 Bile Acid Sequestration Accelerates Glucagon Receptor-Mediated Body Weight Loss in Obese Mice

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss. Previously, we reported that chronic glucagon receptor (GCGR) activation increased energy expenditure and plasma bile acid (BA) levels. Hepatic Farnesoid X Receptor (FXR) has been associated with this GCGR-BA pathway, and liver-specific FXR-deficient mice showed diminished response to the anti-obesity effects of GCGR agonism as compared to WT mice (Diabetes 2018 PMID: 29925501). In this study we hypothesized that BAs play an important role in GCGR-mediated weight loss. To test this, we utilized an anion-exchange BA-binding resin (BABR, cholestyramine or Questran, SANDOZ Inc.) known to reduce plasma total cholesterol, LDL, and BAs. Diet-induced obese C57BL6 mice were weight stable during the 10 d Cholestyramine pretreatment (1.5% in high fat diet 58 kcal%). Daily administration of GCGR agonist, IUB288 (10 nmol/kg, s.c.), for 14 d reduced body weight by 15%; whereas IUB288+Cholestyramine doubled this effect (30%, 2-way ANOVA Time p<0.0001; Drug p=0.019; Time x Drug interaction p<0.0001). As expected, plasma cholesterol was reduced by BABR. However, unexpectedly total BA levels were increased in plasma and feces. Thus, suggesting that cholesterol and BA excretion to feces stimulated BA synthesis and increased whole body energy expenditure. With cholestyramine treatment was increased to 3%, cholestyramine-dependent body weight loss was observed (p<0.05). Combined with daily IUB288 treatment, body weight was further reduced (Time p<0.0001; Drug p=0.0009; Time x Drug interaction p<0.0001). Together, these studies suggest a combination of BABR and GCGR agonism as a novel therapeutic approach for obesity. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.