Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40*
Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40*
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共轭亚油酸通过胰岛 G 蛋白偶联受体 FFA1/GPR40* 介导胰岛素释放
DOI：
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发表时间：
2011
影响因子：
4.8
通讯作者：
E. Kostenis
中科院分区：
文献类型：
--
作者：
Johannes Schmidt;Kathrin Liebscher;Nicole Merten;Manuel Grundmann;M. Mielenz;H. Sauerwein;E. Christiansen;M. E. Due;T. Ulven;S. Ullrich;J. Gomeza;C. Drewke;E. Kostenis
在膳食成分中，共轭亚油酸（CLAs）因其能减少脂肪储存和增加肌肉质量而受到西方国家的广泛关注。然而，一些不良反应也归因于CLAs的摄入，如胰岛素抵抗的加剧和患糖尿病的风险。然而，CLAs对葡萄糖稳态影响的机制尚不完全清楚。在此，我们提供证据表明CLAs特异性激活细胞表面受体FFA1，这是治疗2型糖尿病的新兴治疗靶点。使用不同的重组细胞系统来稳定表达FFA1，以及一系列不同的功能分析，包括新型的无标记非侵入性动态质量重分配技术（康宁®Epic®生物传感器），CLA异构体顺式-9，反式-11-CLA和反式-10，顺式-12-CLA，在体外激活FFA1，其浓度足以解释FFA1在体内的激活。在内源性表达FFA1的胰岛素生成INS-1E细胞和野生型而非FFA1 - / -敲除小鼠的原代胰腺β-细胞中，CLA各异构体均显著增加葡萄糖刺激的胰岛素分泌。我们的研究结果建立了CLAs与胰岛素产生之间的明确机制联系，并确定细胞表面受体FFA1是CLAs的分子靶点，解释了CLAs在体内对胰岛素分泌的急性刺激作用。CLAs也被发现是广泛应用的营养保健品中的胰岛素促胰岛素成分，这一发现对开发治疗2型糖尿病的FFA1调节剂具有重要意义。
Among dietary components, conjugated linoleic acids (CLAs) have attracted considerable attention as weight loss supplements in the Western world because they reduce fat stores and increase muscle mass. However, a number of adverse effects are also ascribed to the intake of CLAs such as aggravation of insulin resistance and the risk of developing diabetes. However, the mechanisms accounting for the effects of CLAs on glucose homeostasis are incompletely understood. Herein we provide evidence that CLAs specifically activate the cell surface receptor FFA1, an emerging therapeutic target to treat type 2 diabetes. Using different recombinant cellular systems engineered to stably express FFA1 and a set of diverse functional assays including the novel, label-free non-invasive dynamic mass redistribution technology (Corning® Epic® biosensor), both CLA isomers cis-9, trans-11-CLA and trans-10, cis-12-CLA were found to activate FFA1 in vitro at concentrations sufficient to also account for FFA1 activation in vivo. Each CLA isomer markedly increased glucose-stimulated insulin secretion in insulin-producing INS-1E cells that endogenously express FFA1 and in primary pancreatic β-cells of wild type but not FFA1−/− knock-out mice. Our findings establish a clear mechanistic link between CLAs and insulin production and identify the cell surface receptor FFA1 as a molecular target for CLAs, explaining their acute stimulatory effects on insulin secretion in vivo. CLAs are also revealed as insulinotropic components in widely used nutraceuticals, a finding with significant implication for development of FFA1 modulators to treat type 2 diabetes.
DOI：
10.1111/j.1463-1326.2009.01114.x
发表时间：
2009-11
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Kebede MA;Alquier T;Latour MG;Poitout V
通讯作者：
Poitout V
影响因子：
46.9
作者：
Schroeder, Ralf;Janssen, Nicole;Kostenis, Evi
通讯作者：
Kostenis, Evi
影响因子：
7.7
作者：
Ryder, JW;Portocarrero, CP;Houseknecht, KL
通讯作者：
Houseknecht, KL