Long-Acting GIPR Agonism Enhances Body Weight Regulation of Multiple Weight-Reducing Agents in Diet-Induced Obese Mice

The development of multi-agonists targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) has resulted in significant clinical improvements in body weight management, however the contribution of GIPR agonism to this effect is incompletely understood. Using a diet induced obese (DIO) mouse model, GIPR agonism (LAGIPRA) alone has demonstrated little to no efficacy in weight management, whereas the addition of LAGIPRA to long acting GLP-1R agonism decreased food intake and increased energy expenditure resulting in greater weight loss compared with GLP-1R agonism alone suggesting a synergistic benefit. To determine whether GIPR agonism would provide similar synergistic improvements in energy metabolism with additional pharmacologic drivers of weight loss, we treated DIO mice with various weight reducing agents plus and minus LAGIPRA in metabolic chambers. Interestingly, addition of LAGIPRA enhanced weight loss, fat mass reduction, energy expenditure, and lipid oxidation whether combined with T3, FGF21, or long-acting glucagon (IUB288); consistent with earlier experiments, it had little effect on its own. Assessment of adipose tissue engagement in these and subsequent studies suggest GIPR agonism in this tissue may enhance lipolysis, potentially enabling greater energy expenditure via release of stored lipids. These findings suggest a unique role for GIPR agonism to regulate energy expenditure when combined with molecules that reduce body weight generating a greater negative caloric balance and enhancing body weight reduction. Disclosure W.Roell: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. L.O'farrell: None. A.Regmi: Employee; Eli Lilly and Company. T.Coskun: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.