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. 2025 Jan 7;37(1):187-204.e7.
doi: 10.1016/j.cmet.2024.11.003. Epub 2024 Dec 5.

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

Xinxin Yu  1 , Shiuhwei Chen  1 , Jan-Bernd Funcke  1 , Leon G Straub  1 , Valentina Pirro  2 , Margo P Emont  3 , Brian A Droz  2 , Kyla Ai Collins  2 , Chanmin Joung  1 , Mackenzie J Pearson  2 , Corey M James  2 , Gopal J Babu  4 , Vissarion Efthymiou  5 , Ashley Vernon  6 , Mary Elizabeth Patti  5 , Yu A An  7 , Evan D Rosen  3 , Matthew P Coghlan  2 , Ricardo J Samms  2 , Philipp E Scherer  1 , Christine M Kusminski  8
Affiliations

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

Xinxin Yu et al. Cell Metab. .

Abstract

Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (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. Although 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.

Keywords: GIP receptor; SERCA pathway; adipose tissue; energy expenditure; obesity; weight loss.

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Conflict of interest statement

Declaration of interests R.J.S., V.P., K.A.C., C.J., and M.C. are current or past employees of Eli Lilly and Company. This does not alter the authors’ adherence to science journal policies on sharing data and materials.

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