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.

中文翻译：

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GIP 受体激活白色脂肪组织中徒劳的钙循环，以增加能量消耗并驱动小鼠体重减轻


肥胖是一种慢性疾病，会导致胰岛素抵抗、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，葡萄糖依赖性促胰岛素多肽 （GIP） 受体 （GIPR） 和胰高血糖素样肽-1 （GLP-1） 受体 （GLP-1R） 共激动剂为 T2D 和肥胖症患者提供了更好的治疗效果。尽管 GLP-1R 激动作用的代谢益处已确定，但 GIPR 激活是否通过外周机制影响体重减轻尚未完全定义。在这里，我们生成了一个仅在脂肪细胞中诱导 GIPR 的小鼠模型。我们表明，脂肪细胞中的 GIPR 诱导可保护小鼠免受饮食诱导的肥胖，并在肥胖环境中触发严重的体重减轻 （∼35%）。脂肪 GIPR 进一步增加脂质氧化、产热和能量消耗。从机制上讲，我们证明 GIPR 诱导激活脂肪细胞中 SERCA 介导的徒劳钙循环。GIPR 激活进一步触发代谢记忆效应，在转基因关闭后维持体重减轻，突出了脂肪细胞生物学的一个独特方面。总的来说，我们提出了一种外周 GIPR 在脂肪组织中起作用的机制，它对体重和能量平衡产生有益的代谢影响。