1965-P: Glucagon Receptor Agonism Stimulates Body Weight Loss in Antibiotic Treatment in Obese Mice

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss in diet-induced obese (DIO) mice. Glucagon’s role as a primary counterregulatory hormone to insulin action has long received scientific attention, yet its broader therapeutic potential is an evolving research interest. We reported that chronic glucagon receptor (GCGR) activation increased energy expenditure and plasma bile acids (BA) in an farnesoid X receptor (FXR) dependent manner. Glucagon stimulates the conversion of cholesterol to BAs, with an increase in cholic and chenodeoxycholate species, critical regulators of FXR activity. Gut microbiota are known to alter the chemical structure of bile acids to produce secondary and tertiary BA. Thus, in these studies we tested the hypothesis that GCGR agonism regulates the gut microbiome to alter circulating BAs and stimulate FXR. GCGR agonism stimulated a profound change in the gut microbiome of DIO mice. These changes were largely associated with an increase in Actinobacteria and a decrease in Deferribacteria phylums. Assessment of functional microbiome composition via PICRUSt uncovered significant impacts on 130 out of 160 total KEGG pathways, including those involved in BA synthesis. To investigate the role of the gut microbiome on GCGR-stimulated weight loss we treated DIO mice with an antibiotic (AB) cocktail (ampicillin, vancomycin, metronidazole, neomycin, and amphotericin B) or vehicle. Mice were then treated with the GCGR agonist, IUB288, or vehicle for 14d to stimulate weight-loss. Surprisingly, AB-treated mice lost a similar amount of body-weight when treated with IUB288, suggesting that the gut microbiome may be dispensable for the weight loss effect. However, post hoc analysis of the cecal microbiome identified only a partial ablation of microbiota in AB-treated mice, with unexpected increases in Proteobacteria and Tenericutes. Thus, it is possible that GCGR-agonism acts via one of the resistant microbes to regulate weight loss.