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. Overall design: 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).