Department of Restorative Neurosurgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Prog Lipid Res. 2015 Apr;58:40-50. doi: 10.1016/j.plipres.2015.01.002. Epub 2015 Jan 20.
G protein-coupled receptor 40 (GPR40), a receptor for diverse non-esterified fatty acids, is expressed predominantly in the wide variety of neurons of the central nervous system and β-cells in the pancreatic islets. Since deorphanization of GPR40 in 2003, the past decade has seen major advances in our understanding of its role in the insulin secretion. However, there is still a great deal to be elucidated about the role of GPR40 in the brain, because the latter shows the most abundant GPR40 mRNA expression among the human tissues. Since a substantial expression of GPR40 is also seen in the hypothalamus, 'brain-lipid sensing' might be involved in the control of insulin secretion and energy balance. The preceding experiments using monkeys after transient global brain ischemia, have highlighted implication of GPR40 for amplifying adult hippocampal neurogenesis. Although GPR40-mediated intracellular signaling was recently found to result in phosphorylation of cAMP response element-binding protein (CREB) necessary for the neuronal differentiation and synaptic plasticity, the signaling cascade is still incompletely understood. Furthermore, in response to conjugated linoleic acids or trans isomers of arachidonic acid, GPR40 was recently demonstrated in rodents to mediate lipotoxicity to β-cells, neurons, or microvessels, which result in diabetes, retinopathy, stroke, etc. However, it still remains undetermined in humans whether and how oxidized, conjugated, or excessive fatty acids evoke lipotoxicity. Although literature about GPR40 is limited especially about the brain or the brain-pancreas interaction, this review aims at summarizing beneficial as well as detrimental effects of this receptor in the brain and pancreas in response to diverse fatty acids.
G 蛋白偶联受体 40（GPR40）是多种非酯化脂肪酸的受体，主要表达于中枢神经系统的各种神经元和胰岛β细胞中。自 2003 年 GPR40 被鉴定以来，过去十年中，人们对其在胰岛素分泌中的作用有了更深入的了解。然而，关于 GPR40 在大脑中的作用仍有许多需要阐明的地方，因为后者在人体组织中显示出最丰富的 GPR40 mRNA 表达。由于 GPR40 在下丘脑也有大量表达，因此“脑脂质感应”可能参与了胰岛素分泌和能量平衡的控制。在对短暂全脑缺血的猴子进行的前期实验中，突显了 GPR40 在放大成年海马神经发生中的作用。尽管最近发现 GPR40 介导的细胞内信号转导导致 cAMP 反应元件结合蛋白（CREB）磷酸化，这对于神经元分化和突触可塑性是必需的，但信号级联仍不完全清楚。此外，最近在啮齿动物中发现，GPR40 可以介导共轭亚油酸或花生四烯酸的反式异构体对β细胞、神经元或微血管的脂毒性，从而导致糖尿病、视网膜病变、中风等。然而，在人类中，是否以及如何氧化、共轭或过量的脂肪酸引发脂毒性仍未确定。尽管关于 GPR40 的文献有限，特别是关于大脑或脑-胰腺相互作用的文献，但本综述旨在总结该受体在大脑和胰腺中对各种脂肪酸的有益和有害影响。
