Raab Susanne, Wang Haiyan, Uhles Sabine, Cole Nadine, Alvarez-Sanchez Ruben, Künnecke Basil, Ullmer Christoph, Matile Hugues, Bedoucha Marc, Norcross Roger D, Ottaway-Parker Nickki, Perez-Tilve Diego, Conde Knape Karin, Tschöp Matthias H, Hoener Marius C, Sewing Sabine
Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
Department of Internal Medicine, Metabolic Disease Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
Mol Metab. 2015 Nov 1;5(1):47-56. doi: 10.1016/j.molmet.2015.09.015. eCollection 2016 Jan.
Type 2 diabetes and obesity are emerging pandemics in the 21st century creating worldwide urgency for the development of novel and safe therapies. We investigated trace amine-associated receptor 1 (TAAR1) as a novel target contributing to the control of glucose homeostasis and body weight.
We investigated the peripheral human tissue distribution of TAAR1 by immunohistochemistry and tested the effect of a small molecule TAAR1 agonist on insulin secretion in vitro using INS1E cells and human islets and on glucose tolerance in C57Bl6, and db/db mice. Body weight effects were investigated in obese DIO mice.
TAAR1 activation by a selective small molecule agonist increased glucose-dependent insulin secretion in INS1E cells and human islets and elevated plasma PYY and GLP-1 levels in mice. In diabetic db/db mice, the TAAR1 agonist normalized glucose excursion during an oral glucose tolerance test. Sub-chronic treatment of diet-induced obese (DIO) mice with the TAAR1 agonist resulted in reduced food intake and body weight. Furthermore insulin sensitivity was improved and plasma triglyceride levels and liver triglyceride content were lower than in controls.
We have identified TAAR1 as a novel integrator of metabolic control, which acts on gastrointestinal and pancreatic islet hormone secretion. Thus TAAR1 qualifies as a novel and promising target for the treatment of type 2 diabetes and obesity.
2型糖尿病和肥胖症是21世纪新出现的大流行病，这使得开发新型安全疗法在全球范围内变得紧迫。我们研究了痕量胺相关受体1（TAAR1）作为有助于控制葡萄糖稳态和体重的新靶点。
我们通过免疫组织化学研究了TAAR1在人体外周组织中的分布，并使用INS1E细胞和人胰岛在体外测试了一种小分子TAAR1激动剂对胰岛素分泌的影响，以及对C57Bl6和db/db小鼠葡萄糖耐量的影响。在肥胖的饮食诱导肥胖（DIO）小鼠中研究了体重影响。
选择性小分子激动剂激活TAAR1可增加INS1E细胞和人胰岛中葡萄糖依赖性胰岛素分泌，并提高小鼠血浆PYY和GLP-1水平。在糖尿病db/db小鼠中，TAAR1激动剂在口服葡萄糖耐量试验期间使血糖波动恢复正常。用TAAR1激动剂对饮食诱导肥胖（DIO）小鼠进行亚慢性治疗可导致食物摄入量和体重降低。此外，胰岛素敏感性得到改善，血浆甘油三酯水平和肝脏甘油三酯含量低于对照组。
我们已确定TAAR1是代谢控制的新型整合因子，作用于胃肠道和胰岛激素分泌。因此，TAAR1有资格成为治疗2型糖尿病和肥胖症的新型且有前景的靶点。
