Glucose-dependent insulinotropic polypeptide receptor signaling in oligodendrocytes increases the weight-loss action of GLP-1R agonism
Cell Metabolism. 2025-08-01; :
DOI: 10.1016/j.cmet.2025.07.009
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https://www.bordeaux-neurocampus.fr/11961
Hansford R(1), Buller S(1), Tsang AH(1), Benoit S(1), Roberts AG(2), Erskine
E(1), Brown T(1), Pirro V(3), Reimann F(1), Harada N(4), Inagaki N(4), Samms
RJ(3), Broichhagen J(5), Hodson DJ(6), Adriaenssens A(2), Park S(3), Blouet
C(7).
Author information:
(1)Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital,
Cambridge CB20QQ, UK.
(2)Department of Neuroscience, Physiology, and Pharmacology, University College
London, London, UK.
(3)Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly
and Company, Indianapolis, IN, USA.
(4)Department of Diabetes, Endocrinology and Nutrition, Kyoto University, Kyoto,
Japan.
(5)Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin,
Germany.
(6)Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford
Biomedical Research Centre, Churchill Hospital, Radcliffe Department of
Medicine, University of Oxford, Oxford, UK.
(7)Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital,
Cambridge CB20QQ, UK. Electronic address: .
The next generation of obesity medicines harness the activity of the
glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1
receptors (GIPR and GLP-1R), but their mechanism of action remains unclear.
Here, we report that the GIPR is enriched in oligodendrocytes and GIPR signaling
bidirectionally regulates oligodendrogenesis. In mice with adult-onset deletion
of GIPR in oligodendrocytes, GIPR agonism fails to enhance the weight-loss
effects of GLP-1R agonism. Mechanistically, GIPR agonism increases brain access
of GLP-1R agonists, and GIPR signaling in oligodendrocytes is required for this
effect. In addition, we show that vasopressin neurons of the paraventricular
hypothalamus are necessary for the weight-loss response to GLP-1R activation,
targeted by peripherally administered GLP-1R agonists via their axonal
compartment, and this access is increased by activation of the GIPR in
oligodendrocytes. Collectively, our findings identify a novel mechanism by which
incretin therapies may function to promote synergistic weight loss in the
management of excess adiposity.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cmet.2025.07.009
PMID: 40812310
Conflict of interest statement: Declaration of interests R.J.S., S.P., and V.P.
are employees and shareholders of Eli Lilly and Company. D.J.H. and J.B. have
filed a patent on GLP-1R and GIPR chemical probes. D.J.H. and J.B. received
licensing revenue from Celtarys Research for provision of GLP-1R/GIPR chemical
probes. D.J.H. has filed patents related to type 2 diabetes therapy and GLP-1R
agonism.