德国亥姆霍兹糖尿病研究中心Timo D. Müller课题组发现，葡萄糖依赖性促胰岛素多肽（GIP）通过CNS-GIPR信号传导调节体重和食物摄入。2021年4月6日出版的《细胞—代谢》杂志发表了这项成果。

研究人员表示，对于治疗肥胖症，是否应激活或抑制葡萄糖依赖性促胰岛素多肽受体（GIPR）存在不确定性。Gipr最近在下丘脑摄食中枢得到证实，但中枢神经系统（CNS）Gipr的生理相关性仍未知。

研究人员发现，高脂饮食（HFD）喂养的CNS-Gipr KO小鼠以及具有CNS-hGIPR缺失的人源化（h）GIPR敲入小鼠显示出体重减轻和葡萄糖代谢改善。在饮食诱导肥胖（DIO）小鼠中，急性中枢和外周给予酰基GIP会增加下丘脑摄食中枢的cFos神经元活性，这与体重和食物摄入减少以及葡萄糖处理改善相吻合。

长期对酰基GIP进行中枢和外周给药可降低野生型小鼠的体重和食物摄入量，但在CNS-Gipr KO小鼠中显示弱/无功效。而且，在CNS-Gipr KO小鼠中，相对于GLP-1，GLP-1/GIP共激动作用的代谢优势作用消失了。因此，这些数据确立了CNS Gipr在控制能量代谢中的关键作用。 

附：英文原文

Title: The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling

Author: Qian Zhang, Challa Tenagne Delessa, Robert Augustin, Mostafa Bakhti, Gustav Colldén, Daniel J. Drucker, Annette Feuchtinger, Cristina Garcia Caceres, Gerald Grandl, Alexandra Harger, Stephan Herzig, Susanna Hofmann, Cassie Lynn Holleman, Martin Jastroch, Susanne Keipert, Maximilian Kleinert, Patrick J. Knerr, Konxhe Kulaj, Beata Legutko, Heiko Lickert, Xue Liu, Gerd Luippold, Dominik Lutter, Emilija Malogajski, Marta Tarquis Medina, Stephanie A. Mowery, Andreas Blutke, Diego Perez-Tilve, Ciro Salinno, Laura Sehrer, Richard D. DiMarchi, Matthias H. Tschp, Kerstin Stemmer, Brian Finan, Christian Wolfrum, Timo D. Müller

Issue&Volume: 2021/04/06

Abstract: Uncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypothalamic feeding centers, but the physiological relevance of CNS Gipr remains unknown. Here we show that HFD-fed CNS-Gipr KO mice and humanized (h)GIPR knockin mice with CNS-hGIPR deletion show decreased body weight and improved glucose metabolism. In DIO mice, acute central and peripheral administration of acyl-GIP increases cFos neuronal activity in hypothalamic feeding centers, and this coincides with decreased body weight and food intake and improved glucose handling. Chronic central and peripheral administration of acyl-GIP lowers body weight and food intake in wild-type mice, but shows blunted/absent efficacy in CNS-Gipr KO mice. Also, the superior metabolic effect of GLP-1/GIP co-agonism relative to GLP-1 is extinguished in CNS-Gipr KO mice. Our data hence establish a key role of CNS Gipr for control of energy metabolism.

DOI: 10.1016/j.cmet.2021.01.015

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00015-2