Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion.
Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion.
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作者：
Edfalk S;Steneberg P;Edlund H
目的：g蛋白偶联受体Gpr40在β细胞中表达，参与游离脂肪酸（FFA）增强葡萄糖刺激的胰岛素分泌。然而，Gpr40的其他表达位点，包括肠道，已经被提出。转录因子IPF1/PDX1最近被证明与Gpr40 5 '侧区域的一个增强子元件结合，这意味着IPF1/PDX1可能调节Gpr40的表达。在这里，我们研究了1)Gpr40是否在肠道中表达，以及2)Gpr40的表达是否需要Ipf1/Pdx1功能。研究设计与方法：本研究采用Gpr40报告小鼠X-gal染色法和原位杂交法监测Gpr40的表达。使用Ipf1/Pdx1-null和β细胞特异性突变体来研究Ipf1/Pdx1是否控制Gpr40的表达。测定Gpr40突变小鼠和对照小鼠血浆胰岛素、葡萄糖依赖性胰岛素性多肽（GIP）、胰高血糖素样肽-1 （GLP-1）和葡萄糖水平对急性口服脂肪饮食的反应。结果：我们发现Gpr40在胃肠道内分泌细胞中表达，包括表达肠促胰岛素激素GLP-1和GIP的细胞，Gpr40介导ffa刺激的肠促胰岛素分泌。我们还发现Ipf1/Pdx1是Gpr40在前胃肠道β细胞和内分泌细胞中表达所必需的。总之，我们的数据提供了证据，证明Gpr40不仅直接而且间接地通过调节促肠促胰岛素分泌调节fa刺激的β细胞的胰岛素分泌。此外，我们的数据表明Ipf1/Pdx1和Gpr40在fa介导的调节葡萄糖和整体能量稳态的激素分泌中起保守作用。
OBJECTIVE—The G-protein–coupled receptor Gpr40 is expressed in β-cells where it contributes to free fatty acid (FFA) enhancement of glucose-stimulated insulin secretion. However, other sites of Gpr40 expression, including the intestine, have been suggested. The transcription factor IPF1/PDX1 was recently shown to bind to an enhancer element within the 5′-flanking region of Gpr40, implying that IPF1/PDX1 might regulate Gpr40 expression. Here, we addressed whether 1) Gpr40 is expressed in the intestine and 2) Ipf1/Pdx1 function is required for Gpr40 expression. RESEARCH DESIGN AND METHODS—In the present study, Gpr40 expression was monitored by X-gal staining using Gpr40 reporter mice and by in situ hybridization. Ipf1/Pdx1-null and β-cell specific mutants were used to investigate whether Ipf1/Pdx1 controls Gpr40 expression. Plasma insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucose levels in response to acute oral fat diet were determined in Gpr40 mutant and control mice. RESULTS—Here, we show that Gpr40 is expressed in endocrine cells of the gastrointestinal tract, including cells expressing the incretin hormones GLP-1 and GIP, and that Gpr40 mediates FFA-stimulated incretin secretion. We also show that Ipf1/Pdx1 is required for expression of Gpr40 in β-cells and endocrine cells of the anterior gastrointestinal tract. CONCLUSIONS—Together, our data provide evidence that Gpr40 modulates FFA-stimulated insulin secretion from β-cells not only directly but also indirectly via regulation of incretin secretion. Moreover, our data suggest a conserved role for Ipf1/Pdx1 and Gpr40 in FFA-mediated secretion of hormones that regulate glucose and overall energy homeostasis.
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影响因子：
2.6
作者：
Larsson, LI;Madsen, OD;Edlund, H
通讯作者：
Edlund, H
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Edlund, H
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