美国德克萨斯大学Christine M. Kusminski课题组发现，GIP受体在小鼠白色脂肪组织中激活无效钙循环来增加能量消耗并促进体重减轻。2024年12月5日，《细胞—代谢》杂志在线发表了这项成果。

研究人员表示，肥胖是一种慢性疾病，促使胰岛素抵抗、2型糖尿病（T2D）和心血管风险的发展。与选择性GLP-1R激动剂相比，葡萄糖依赖性胰岛素促分泌多肽（GIP）受体（GIPR）和胰高血糖素样肽-1（GLP-1）受体（GLP-1R）共同激动在T2D和肥胖个体中提供了更好的治疗效果。尽管GLP-1R激动剂的代谢益处已被确立，但GIPR激活是否通过外周机制影响体重减轻尚未完全定义。

研究人员生成了一个仅在脂肪细胞中诱导GIPR的小鼠模型。研究表明，脂肪细胞中GIPR的诱导能够保护小鼠免受饮食诱导的肥胖，并在肥胖环境中引发显著的体重减轻（约35%）。脂肪组织中的GIPR进一步增加了脂质氧化、产热和能量消耗。从机制上讲，研究人员证明GIPR诱导激活了脂肪细胞中由SERCA介导的无效钙循环。GIPR激活还触发了一种代谢记忆效应，即在转基因关闭后维持体重减轻，突显了脂肪细胞生物学中的一个独特方面。

总体而言，研究人员呈现了外周GIPR在脂肪组织中的作用机制，它对体重和能量平衡产生有益的代谢效应。

附：英文原文

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

Author: Xinxin Yu, Shiuhwei Chen, Jan-Bernd Funcke, Leon G. Straub, Valentina Pirro, Margo P. Emont, Brian A. Droz, Kyla AI. Collins, Chanmin Joung, Mackenzie J. Pearson, Corey M. James, Gopal J. Babu, Vissarion Efthymiou, Ashley Vernon, Mary Elizabeth Patti, Yu A. An, Evan D. Rosen, Matthew P. Coghlan, Ricardo J. Samms, Philipp E. Scherer, Christine M. Kusminski

Issue&Volume: 2024-12-05

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.

DOI: 10.1016/j.cmet.2024.11.003

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00449-2