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. We show that HFD-fed CNS-Gipr ko mice and humanized (h)GIPR knock-in mice with CNS-hGIPR deletion show improved body weight and glycemia, but these metabolic improvements vanish upon adult-onset Gipr deletion. In DIO mice, acute central administration of acyl-GIP increases cFos neuronal activity in the arcuate, dorsomedial, paraventricular and lateral hypothalamus and leads to improved body weight, food intake, and glycemia. Chronic administration of acyl-GIP improves body weight and food intake in wildtype 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 was extinguished in CNS-Gipr ko mice. Our data establish a key role of CNS Gipr for control of energy metabolism.
Zhang, Qian and Delessa, Challa Tenagne and Augustin, Robert and Bakhti, Mostafa and Colldén, Gustav and Drucker, Daniel J. and Feuchtinger, Annette and Caceres, Cristina Garcia and Grandl, Gerald and Harger, Alexandra and Hofmann, Susanna and Hollemann, Cassie Lynn and Kleinert, Maximilian and Knerr, Patrick J. and Kulaj, Konxhe and Legutko, Beata and Lickert, Heiko and Liu, Xue and Luippold, Gerd and Malogajski, Emilija and Medina, Marta Tarquis and Mowery, Stephanie and Parzefall, Andreas and Perez-Tilve, Diego and Salinno, Ciro and Sehrer, Laura and DiMarchi, Richard D. and Tschöp, Matthias H. and Stemmer, Kerstin and Finan, Brian and Wolfrum, Christian and Müller, Timo D., The Glucose-Dependent Insulinotropic Polypeptide (GIP) Regulates Body Weight and Food Intake Via CNS-GIPR Signaling. Available at SSRN: https://ssrn.com/abstract=3667144 or http://dx.doi.org/10.2139/ssrn.3667144
This version of the paper has not been formally peer reviewed.
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