Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
FASEB J. 2011 Nov;25(11):3803-14. doi: 10.1096/fj.11-184531. Epub 2011 Jul 22.
GPR39, a constitutively active 7TM receptor important for glucose-induced insulin secretion and maturation of pancreatic β-cell function, is up-regulated in adipose tissue on abstinence from food and chemically induced diabetes. In the present study, we investigated the effect of GPR39 deficiency on body weight and adipocyte metabolism. GPR39-deficient mice were subjected to a high-fat diet and body composition, glucose tolerance, insulin secretion, food intake, and energy expenditure were evaluated. The cell biology of adipocyte metabolism was studied on both mRNA and protein levels. A significant increase in body weight corresponding to a 2-fold selective increase in fat mass was observed in GPR39-deficient mice fed a high-fat diet as compared with wild-type littermate controls fed the same diet. The GPR39-deficient animals had similar food intake but displayed almost eliminated diet-induced thermogenesis, measured by the oxygen consumption rate (Vo(2)) on change from normal to high-fat diet. Analysis of the adipose tissue for lipolytic enzymes demonstrated decreased level of phosphorylated hormone-sensitive lipase (HSL) and a decreased level of adipose triglyceride lipase (ATGL) by 35 and 60%, respectively, after food withdrawal in the GPR39-deficient mice. Extracellular signal-regulated kinases (ERK1/2), a signaling pathway known to be important for lipolysis, was decreased by 56% in the GPR39-deficient mice. GPR39 deficiency is associated with increased fat accumulation on a high-fat diet, conceivably due to decreased energy expenditure and adipocyte lipolytic activity.
GPR39 是一种组成型激活的 7TM 受体，对于葡萄糖诱导的胰岛素分泌和胰腺β细胞功能的成熟很重要，在禁食和化学诱导的糖尿病中，其在脂肪组织中上调。在本研究中，我们研究了 GPR39 缺失对体重和脂肪细胞代谢的影响。将 GPR39 缺陷型小鼠置于高脂肪饮食中，并评估了其身体成分、葡萄糖耐量、胰岛素分泌、摄食量和能量消耗。还在 mRNA 和蛋白水平上研究了脂肪细胞代谢的细胞生物学。与同饮食喂养的野生型对照相比，GPR39 缺陷型小鼠在高脂肪饮食喂养时体重显著增加，相应地脂肪量增加了 2 倍。GPR39 缺陷型动物的摄食量相似，但在从正常饮食改为高脂肪饮食时，其饮食诱导的产热几乎消除，通过耗氧量（Vo2）来测量。对脂肪组织中脂肪分解酶的分析表明，在禁食后，GPR39 缺陷型小鼠的磷酸化激素敏感脂肪酶（HSL）水平降低了 35%，脂肪甘油三酯脂肪酶（ATGL）水平降低了 60%。已知对外界信号调节激酶（ERK1/2）是脂肪分解的重要信号通路，在 GPR39 缺陷型小鼠中降低了 56%。GPR39 缺失与高脂肪饮食中脂肪积累增加有关，这可能是由于能量消耗和脂肪细胞脂肪分解活性降低所致。
