The Role of beta-Hydroxybutyrate in Glucagon Receptor Stimulated Food Intake Suppression in Obese Mice

Glucagon’s counterregulatory role to insulin action is well known, but its broader therapeutic potential is an evolving research interest. We have reported that chronic glucagon receptor (GCGR) activation decreases body weight (BW) and food intake (FI) while increasing beta-Hydroxybutyrate (bHB), a known ketone body. Recent studies suggest that ketone esters similarly reduce food intake in mice. The primary objective of this study was to determine if decreases in FI seen in DIO mice treated with GCGR agonist (IUB288) are mediated by bHB. C57Bl6/J mice were fed High Fat Diet (HFD, 58% fat + sucrose) for 12 weeks, to stimulate diet induced obesity. Mice were assigned into groups matched for food intake; Vehicle-Vehicle, Vehicle-IUB288, Trimetazidine-Vehicle, Trimetazidine-IUB288, (n=3). Mice were treated with or without Trimetazidine, 15 mg/kg (TMZ), an inhibitor of ketogenesis, for two days prior to four days of IUB288 or vehicle injections. Following a ten-day wash out period, the study was repeated using 30 mg/kg. FI and BW were measured daily, and plasma bHB were measured at baseline and study conclusion. IUB288 reduced FI and BW in both TMZ and vehicle treated mice. Surprisingly bHB concentration was elevated post-treatment in both 15 mg/kg and 30 mg/kg TMZ treated mice. In both experiments, the administered dosage of TMZ was insufficient to block IUB288-stimulated bHB. The results provide neither evidence for, or against, bHB FI suppression in DIO mice. Future studies will utilize a larger dosage of TMZ, or administration of a different inhibitor of ketogenesis