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

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 t...

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Detalles Bibliográficos
Autores principales: Zhang, Qian, Delessa, Challa Tenagne, Augustin, Robert, Bakhti, Mostafa, Colldén, Gustav, Drucker, Daniel J., Feuchtinger, Annette, Caceres, Cristina Garcia, Grandl, Gerald, Harger, Alexandra, Herzig, Stephan, Hofmann, Susanna, Holleman, Cassie Lynn, Jastroch, Martin, Keipert, Susanne, Kleinert, Maximilian, Knerr, Patrick J., Kulaj, Konxhe, Legutko, Beata, Lickert, Heiko, Liu, Xue, Luippold, Gerd, Lutter, Dominik, Malogajski, Emilija, Medina, Marta Tarquis, Mowery, Stephanie A., Blutke, Andreas, Perez-Tilve, Diego, Salinno, Ciro, Sehrer, Laura, DiMarchi, Richard D., Tschöp, Matthias H., Stemmer, Kerstin, Finan, Brian, Wolfrum, Christian, Müller, Timo D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035082/
https://www.ncbi.nlm.nih.gov/pubmed/33571454
http://dx.doi.org/10.1016/j.cmet.2021.01.015
Descripción
Sumario: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.