The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice

Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. While the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined. Here, we generated a mouse model of GIPR induction exclusively in the adipocyte. We show that GIPR induction in the fat cell protects mice from diet-induced obesity and triggers profound weight loss (~35%) in an obese setting. Adipose GIPR further increases lipid oxidation, thermogenesis and energy expenditure. Mechanistically, we demonstrate that GIPR induction activates SERCA-mediated futile calcium cycling in the adipocyte. GIPR activation further triggers a metabolic memory effect, which maintains weight loss after the transgene has been switched off, highlighting a unique aspect in adipocyte biology. Collectively, we present a mechanism of peripheral GIPR action in adipose tissue, which exerts beneficial metabolic effects on body weight and energy balance. To examine the in vivo effects of inducing the GIPR in white fat on weight loss and energy balance, we performed RNA sequencing on subcutaneous adipose tissue from wild-type (WT) control mice and inducible adipose tissue-specific TRE-GIPR-Adip (GA) mice. This was to evaluate transcriptional changes in adipose tissue following feeding of Doxycycline-diet containing high fat-diet (Dox-HFD) to all mice for 2 weeks (i.e., GIPR transgene induction in adipose tissue).