TY - JOUR
T1 - The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling
AU - Zhang, Qian
AU - Delessa, Challa Tenagne
AU - Augustin, Robert
AU - Bakhti, Mostafa
AU - Colldén, Gustav
AU - Drucker, Daniel J.
AU - Feuchtinger, Annette
AU - Caceres, Cristina Garcia
AU - Grandl, Gerald
AU - Harger, Alexandra
AU - Herzig, Stephan
AU - Hofmann, Susanna
AU - Holleman, Cassie Lynn
AU - Jastroch, Martin
AU - Keipert, Susanne
AU - Kleinert, Maximilian
AU - Knerr, Patrick J.
AU - Kulaj, Konxhe
AU - Legutko, Beata
AU - Lickert, Heiko
AU - Liu, Xue
AU - Luippold, Gerd
AU - Lutter, Dominik
AU - Malogajski, Emilija
AU - Medina, Marta Tarquis
AU - Mowery, Stephanie A.
AU - Blutke, Andreas
AU - Perez-Tilve, Diego
AU - Salinno, Ciro
AU - Sehrer, Laura
AU - DiMarchi, Richard D.
AU - Tschöp, Matthias H.
AU - Stemmer, Kerstin
AU - Finan, Brian
AU - Wolfrum, Christian
AU - Müller, Timo D.
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/4/6
Y1 - 2021/4/6
N2 - 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.
AB - 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.
KW - CNS
KW - GIP
KW - GIPR CNS KO
KW - body weight
KW - diet-induced obesity
KW - food intake
KW - glucose metabolism
KW - incretin
KW - type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85101716742&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2021.01.015
DO - 10.1016/j.cmet.2021.01.015
M3 - Article
C2 - 33571454
AN - SCOPUS:85101716742
SN - 1550-4131
VL - 33
SP - 833-844.e5
JO - Cell Metabolism
JF - Cell Metabolism
IS - 4
ER -
