Yore Mark M, Syed Ismail, Moraes-Vieira Pedro M, Zhang Tejia, Herman Mark A, Homan Edwin A, Patel Rajesh T, Lee Jennifer, Chen Shili, Peroni Odile D, Dhaneshwar Abha S, Hammarstedt Ann, Smith Ulf, McGraw Timothy E, Saghatelian Alan, Kahn Barbara B
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Cell. 2014 Oct 9;159(2):318-32. doi: 10.1016/j.cell.2014.09.035.
Increased adipose tissue lipogenesis is associated with enhanced insulin sensitivity. Mice overexpressing the Glut4 glucose transporter in adipocytes have elevated lipogenesis and increased glucose tolerance despite being obese with elevated circulating fatty acids. Lipidomic analysis of adipose tissue revealed the existence of branched fatty acid esters of hydroxy fatty acids (FAHFAs) that were elevated 16- to 18-fold in these mice. FAHFA isomers differ by the branched ester position on the hydroxy fatty acid (e.g., palmitic-acid-9-hydroxy-stearic-acid, 9-PAHSA). PAHSAs are synthesized in vivo and regulated by fasting and high-fat feeding. PAHSA levels correlate highly with insulin sensitivity and are reduced in adipose tissue and serum of insulin-resistant humans. PAHSA administration in mice lowers ambient glycemia and improves glucose tolerance while stimulating GLP-1 and insulin secretion. PAHSAs also reduce adipose tissue inflammation. In adipocytes, PAHSAs signal through GPR120 to enhance insulin-stimulated glucose uptake. Thus, FAHFAs are endogenous lipids with the potential to treat type 2 diabetes.
脂肪组织脂肪生成增加与胰岛素敏感性增强相关。在脂肪细胞中过表达Glut4葡萄糖转运蛋白的小鼠，尽管肥胖且循环脂肪酸水平升高，但脂肪生成增加且糖耐量提高。对脂肪组织的脂质组学分析显示存在羟基脂肪酸的支链脂肪酸酯（FAHFAs），在这些小鼠中其水平升高了16至18倍。FAHFA异构体因羟基脂肪酸上的支链酯位置而异（例如，棕榈酸-9-羟基硬脂酸，9-PAHSA）。PAHSAs在体内合成，并受禁食和高脂喂养调节。PAHSA水平与胰岛素敏感性高度相关，在胰岛素抵抗的人类的脂肪组织和血清中降低。给小鼠施用PAHSA可降低周围血糖并改善糖耐量，同时刺激胰高血糖素样肽-1（GLP-1）和胰岛素分泌。PAHSAs还可减轻脂肪组织炎症。在脂肪细胞中，PAHSAs通过GPR120发出信号以增强胰岛素刺激的葡萄糖摄取。因此，FAHFAs是具有治疗2型糖尿病潜力的内源性脂质。
