Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Nature. 2012 Feb 19;483(7389):350-4. doi: 10.1038/nature10798.
Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. 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. 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.
游离脂肪酸作为营养物质提供了一个重要的能量来源，并在各种细胞过程中充当信号分子。已经鉴定出几种 G 蛋白偶联受体作为游离脂肪酸受体，它们在生理和几种疾病中都很重要。GPR120（也称为 O3FAR1）作为不饱和长链游离脂肪酸的受体发挥作用，在各种生理稳态机制中具有关键作用，如脂肪生成、食欲和食物偏好的调节。在这里，我们发现高脂饮食喂养的 GPR120 缺陷小鼠会发展为肥胖、葡萄糖不耐受和脂肪肝，伴随着脂肪细胞分化和脂肪生成减少以及肝脂肪生成增强。这些小鼠的胰岛素抵抗与脂肪组织中胰岛素信号的降低和炎症的增强有关。在人类中，我们发现肥胖个体的脂肪组织中 GPR120 的表达明显高于瘦对照组。对肥胖个体的 GPR120 外显子测序揭示了一种有害的非 synonymous 突变（p.R270H），它抑制了 GPR120 信号活性。此外，p.R270H 变体增加了欧洲人群肥胖的风险。总的来说，这项研究表明，脂质传感器 GPR120 在感知膳食脂肪方面起着关键作用，因此在人类和啮齿动物的能量平衡控制中起着关键作用。
