Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human
Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human
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DOI：
10.1038/nature10798
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发表时间：
2012-03-15
期刊：
影响因子：
64.8
通讯作者：
Froguel, Philippe
中科院分区：
文献类型：
--
作者：
Ichimura, Atsuhiko;Hirasawa, Akira;Froguel, Philippe
游离脂肪酸作为营养物质提供重要的能量来源，并在各种细胞过程中作为信号分子（1-4）。几种G蛋白偶联受体已被鉴定为在生理学以及几种疾病中重要的游离脂肪酸受体（3，5 -13）。GPR 120（也称为O3 FAR 1）作为不饱和长链游离脂肪酸的受体发挥作用，并在各种生理稳态机制中发挥关键作用，如脂肪生成、食欲调节和食物偏好（5，6，14 -16）。在这里，我们表明，GPR 120缺陷小鼠喂养高脂饮食发展肥胖，葡萄糖耐受不良和脂肪肝，减少脂肪细胞分化和脂肪生成和增强肝脏脂肪生成。这些小鼠的胰岛素抵抗与胰岛素信号传导减少和脂肪组织炎症增强有关。在人类中，我们发现肥胖个体的脂肪组织中GPR 120表达显著高于瘦对照。肥胖受试者的GPR 120外显子测序揭示了抑制GPR 120信号传导活性的有害非同义突变（p.R270H）。此外，p.R270H变异增加了欧洲人群的肥胖风险。总的来说，这项研究表明，脂质传感器GPR 120在检测膳食脂肪方面具有关键作用，因此，在人类和啮齿动物的能量平衡控制中具有关键作用。
Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes(1-4). Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases(3,5-13). GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference(5,6,14-16). Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.