GPR43 Potentiates β-Cell Function in Obesity

被引:170
作者
McNelis, Joanne C. [1 ]
Lee, Yun Sok [1 ]
Mayoral, Rafael [1 ]
van der Kant, Rik [2 ]
Johnson, Andrew M. F. [1 ]
Wollam, Joshua [1 ]
Olefsky, Jerrold M. [1 ]
机构
[1] Univ Calif San Diego, Dept Med, Div Endocrinol & Metab, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
基金
美国国家卫生研究院;
关键词
HIGH-FAT DIET; PROTEIN-COUPLED RECEPTORS; TYPE-2; DIABETES-MELLITUS; GUT MICROBIOTA; INSULIN-RESISTANCE; GLUCOSE CONTROL; MICE; ACIDS; GENE; EXPRESSION;
D O I
10.2337/db14-1938
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The intestinal microbiome can regulate host energy home-ostasis and the development of metabolic disease. Here we identify GPR43, a receptor for bacterially produced short-chain fatty acids (SCFAs), as a modulator of microbiota-host interaction. beta-Cell expression of GPR43 and serum levels of acetate, an endogenous SCFA, are increased with a high-fat diet (HFD). HFD-fed GPR43 knockout (KO) mice develop glucose intolerance due to a defect in insulin secretion. In vitro treatment of isolated murine islets, human islets, and Min6 cells with (S)-2-(4-chlorophenyl)-3,3-dimethyl-N-(5-phenylthiazol-2-yl) butanamide (PA), a specific agonist of GPR43, increased intracellular inositol triphosphate and Ca2+ levels, and potentiated insulin secretion in a GPR43-, G alpha q-, and phospholipase C-dependent manner. In addition, KO mice fed an HFD displayed reduced beta-cell mass and expression of differentiation genes, and the treatment of Min6 cells with PA increased beta-cell proliferation and gene expression. Together these findings identify GPR43 as a potential target for therapeutic intervention.
引用
收藏
页码:3203 / 3217
页数:15
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