Bile Acid Binding Resins Improve Glucagon Receptor Agonist-Mediated Weight Loss in Diet-Induced Obese Mice

Glucagon-receptor (GCGR) agonism reguglates bile acid (BA) metabolism and promotes weight loss in diet-induced obese (DIO) mice. Thus, we hypothesized that BA signaling contributes to GCGR-stimulated weight loss.

To test this hypothesis, we utilized BA-binding resins (BARs; colesevelam [Colsv] and cholestyramine [Cstyr]) to prevent intestinal BA reuptake. DIO C57Bl/6J mice were administered the GCGR agonist IUB288 or vehicle, in the presence or absence of BARs.

To our surprise, combined IUB288 and Colsv treatment reduced body weight and food intake compared to IUB288 or Colsv treatment groups in high fat diet (HFD)-fed mice. Moreover, acute IUB288 + Colsv treatment reduced fasting-stimulated HFD, but not chow, intake compared to IUB288 or Colsv treatments alone. We observed improved glucose homeostasis and reduced plasma cholesterol with combined IUB288 and Colsv, but not Colsv alone. Excitingly, liver steatosis was suppressed with IUB288 but not Colsv alone, and this benefit was further enhanced with combined treatment. Plasma BA profiles were regulated by both IUB288 and Colsv with concomitant modulation of liver and ileum BA regulatory mRNA expression. Similar findings were observed with the first-generation BAR Cstyr.

Together, these studies suggest that BARs enhance the antiobesity effect of GCGR agonism in DIO mice, representing a novel antiobesity strategy.