Merck Research Laboratories, Department of Discovery Technologies, Kenilworth, New Jersey 07033, USA.
J Endocrinol. 2010 Jun;205(3):225-32. doi: 10.1677/JOE-10-0009. Epub 2010 Mar 30.
G-protein-coupled bile acid receptor 1 (GPBAR1/TGR5/M-Bar/GPR131) is a cell surface receptor involved in the regulation of bile acid metabolism. We have previously shown that Gpbar1-null mice are resistant to cholesterol gallstone disease when fed a lithogenic diet. Other published studies have suggested that Gpbar1 is involved in both energy homeostasis and glucose homeostasis. Here, we examine the functional role of Gpbar1 in diet-induced obese mice. We found that body weight, food intake, and fasted blood glucose levels were similar between Gpbar1-null mice and their wild-type (WT) littermates when fed a chow or high-fat diet (HFD) for 2 months. However, insulin tolerance tests revealed improved insulin sensitivity in male Gpbar1(-/-) mice fed chow, but impaired insulin sensitivity when fed a HFD. In contrast, female Gpbar1(-/-) mice exhibited improved insulin sensitivity when fed a HFD compared with their WT littermates. Female Gpbar1(-/-) mice had significantly lower plasma cholesterol and triglyceride levels than their WT littermates on both diets. Male Gpbar1(-/-) mice on HFD displayed increased hepatic steatosis when compared with Gpbar1(+)(/)(+) males and Gpbar1(-/-) females on HFD. These results suggest a gender-dependent regulation of Gpbar1 function in metabolic disease.
G 蛋白偶联胆汁酸受体 1（GPBAR1/TGR5/M-Bar/GPR131）是一种参与胆汁酸代谢调节的细胞表面受体。我们之前已经表明，给予致石饮食时，Gpbar1 基因敲除小鼠不易患胆固醇性胆囊结石病。其他已发表的研究表明，Gpbar1 参与能量稳态和葡萄糖稳态的调节。在这里，我们研究了 Gpbar1 在饮食诱导肥胖小鼠中的功能作用。我们发现，当给予普通饮食或高脂肪饮食（HFD）喂养 2 个月时，Gpbar1 基因敲除小鼠与其野生型（WT）同窝仔之间的体重、食物摄入量和空腹血糖水平相似。然而，胰岛素耐量试验显示，给予普通饮食的雄性 Gpbar1 基因敲除小鼠的胰岛素敏感性得到改善，但给予 HFD 的胰岛素敏感性受损。相比之下，给予 HFD 的雌性 Gpbar1 基因敲除小鼠的胰岛素敏感性较其 WT 同窝仔改善。与 WT 同窝仔相比，给予普通饮食或 HFD 的雌性 Gpbar1 基因敲除小鼠的血浆胆固醇和甘油三酯水平均显著降低。与给予 HFD 的 Gpbar1(+)(/)(+)雄性和 Gpbar1(-/-)雌性小鼠相比，给予 HFD 的雄性 Gpbar1 基因敲除小鼠的肝脂肪变性增加。这些结果表明 Gpbar1 功能在代谢性疾病中存在性别依赖性调节。
