Neuronal loss of TRPM8 leads to obesity and glucose intolerance in male mice
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Objective: Mice with global deletion of the transient receptor potential channel melastatin family member 8 (TRPM8) are obese, and treatment of diet-induced obese (DIO) mice with TRPM8 agonists decrease body weight. Whether TRPM8 signaling regulates energy metabolism via central or peripheral effects is unknow. Here we assessed the metabolic phenotype of mice with either Nestin Cre-mediated neuronal loss of TRPM8, or with deletion of TRPM8 in Advillin Cre positive sensory neurons of the peripheral nervous system (PNS).
Methods: Nestin Cre- and Advillin Cre-Trpm8 knock-out (KO) mice were metabolically phenotyped under chronic exposure to either chow or high-fat diet (HFD), followed by assessment of energy and glucose metabolism.
Results: At room temperature, chow-fed neuronal Trpm8 KO are obese and show decreased energy expenditure when acutely treated with the TRPM8 selective agonist icilin. But body weight of neuronal Trpm8 KO mice is indistinguishable from wildtype controls at thermoneutrality, or when mice are chronically exposed to HFD-feeding. In contrast to previous studies, we show that the TRPM8 agonist icilin has no direct effect on brown adipocytes, but that icilin stimulates energy expenditure, at least in part, via neuronal TRPM8 signaling. We further show that lack of TRPM8 in sensory neurons of the PNS does not lead to a metabolically relevant phenotype.
Conclusions: Our data indicate that obesity in TRPM8-deficient mice is centrally mediated and likely originates from alterations in energy expenditure and/or thermal conductance, but does not depend on TRPM8 signaling in brown adipocytes or sensory neurons of the PVN.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 101714 |
| Tidsskrift | Molecular Metabolism |
| Vol/bind | 72 |
| Antal sider | 10 |
| ISSN | 2212-8778 |
| DOI | |
| Status | Udgivet - 2023 |
| Eksternt udgivet | Ja |
Bibliografisk note
(Ekstern) (In Progress / June 2023)
Funding Information:
TDM received funding from the German Research Foundation ( DFG TRR296, TRR152, SFB1123 and GRK 2816/1 ), the German Center for Diabetes Research (DZD e.V.) and the European Research Council ERC-CoG Trusted no. 101044445 . CGC received funding from the European Research Council ERC STG [AstroNeuroCrosstalk no. 757393 ]. The skillful technical assistance of Xenia Leonardt, Peggy Dörfeld, and Marlene Kilian is highly acknowledged.
Funding Information:
M.H.T. is a member of the scientific advisory board of ERX Pharmaceuticals, Cambridge, MA. He was a member of the Research Cluster Advisory Panel (ReCAP) of the Novo Nordisk Foundation between 2017 and 2019. He attended a scientific advisory board meeting of the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, in 2016. He received funding for his research projects from Novo Nordisk (2016–2020) and Sanofi-Aventis (2012–2019). He was a consultant for Bionorica SE (2013–2017), Menarini Ricerche S. p.A. (2016), and Bayer Pharma AG Berlin (2016). As former Director of the Helmholtz Diabetes Center and the Institute for Diabetes and Obesity at Helmholtz Zentrum München (2011–2018), and since 2018, as CEO of Helmholtz Zentrum München, he has been responsible for collaborations with a multitude of companies and institutions worldwide. In this capacity, he discussed potential projects with and has signed/signs contracts for his institute(s) and for the staff for research funding and/or collaborations with industry and academia worldwide, including, but not limited to, pharmaceutical corporations like Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Medigene, Arbormed, BioSyngen, and others. In this role, he was/is further responsible for commercial technology transfer activities of his institute(s), including diabetes-related patent portfolios of Helmholtz Zentrum München as, e.g., WO/2016/188,932 A2 or WO/2017/194,499 A1. M.H.T. confirms that to the best of his knowledge none of the above funding sources were involved in the preparation of this paper. T.D.M. receives research funding from Novo Nordisk, but these funds are unrelated to the here described work.
Publisher Copyright:
© 2023 The Author(s)
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