Venkat Vangaveti, MSc Ghassan Jarrod, MBChB, FRACP Department of Pathology, School of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia.
Ther Adv Endocrinol Metab. 2010 Aug;1(4):165-75. doi: 10.1177/2042018810381066.
Fatty acids (FAs) are important as metabolic substrates and as structural components of biological membranes. However, they also function as signalling molecules. Recently, a series of G protein-coupled receptors (GPRs) for FAs has been described and characterized. These receptors have differing specificities for FAs of differing chain length and degree of saturation, for FA derivatives such as oleoylethanolamide, and for oxidized FAs. They are a critical component of the body's nutrient sensing apparatus, and small molecule agonists and antagonists of these receptors show considerable promise in the management of diabetes and its complications. Agonists of the long-chain free fatty acid receptors FFAR1 and GPR119 act as insulin secretagogues, both directly and by increasing incretins. Although, drugs acting at short-chain FFA receptors (FFAR2 and FFAR3) have not yet been developed, they are attractive targets as they regulate nutrient balance through effects in the intestine and adipose tissue. These include regulation of the secretion of cholecystokinin, peptide YY and leptin. Finally, GPR132 is a receptor for oxidized FAs, which may be a sensor of lipid overload and oxidative stress, and which is involved in atherosclerosis. Regulation of its signalling pathways with drugs may decrease the macrovascular risk experienced by diabetic patients. In summary, FA receptors are emerging drug targets that are involved in the regulation of nutrient status and carbohydrate tolerance, and modulators of these receptors may well figure prominently in the next generation of antidiabetic drugs.
脂肪酸（FAs）是重要的代谢底物和生物膜的结构组成部分。然而，它们也作为信号分子发挥作用。最近，已经描述和表征了一系列脂肪酸的 G 蛋白偶联受体（GPR）。这些受体对不同链长和饱和度的脂肪酸、脂肪酸衍生物（如油酰乙醇酰胺）和氧化脂肪酸具有不同的特异性。它们是身体营养感应装置的关键组成部分，这些受体的小分子激动剂和拮抗剂在糖尿病及其并发症的治疗中显示出很大的前景。长链游离脂肪酸受体 FFAR1 和 GPR119 的激动剂既是直接作用，也是通过增加肠促胰岛素而作为胰岛素分泌激动剂。尽管尚未开发出作用于短链 FFA 受体（FFAR2 和 FFAR3）的药物，但它们作为调节肠道和脂肪组织中营养平衡的靶点很有吸引力，包括调节胆囊收缩素、肽 YY 和瘦素的分泌。最后，GPR132 是氧化脂肪酸的受体，它可能是脂质过载和氧化应激的传感器，并且与动脉粥样硬化有关。用药物调节其信号通路可能会降低糖尿病患者的大血管风险。总之，FA 受体是新兴的药物靶点，它们参与调节营养状况和碳水化合物耐受性，这些受体的调节剂很可能在下一代抗糖尿病药物中占据重要地位。
