Abstract
Glutamine and glutamate are interconverted by several enzymes and alterations in this metabolic cycle are linked to cardiometabolic traits. Herein, we show that obesity-associated insulin resistance is characterized by decreased plasma and white adipose tissue glutamine-to-glutamate ratios. We couple these stoichiometric changes to perturbed fat cell glutaminase and glutamine synthase messenger RNA and protein abundance, which together promote glutaminolysis. In human white adipocytes, reductions in glutaminase activity promote aerobic glycolysis and mitochondrial oxidative capacity via increases in hypoxia-inducible factor 1α abundance, lactate levels and p38 mitogen-activated protein kinase signalling. Systemic glutaminase inhibition in male and female mice, or genetically in adipocytes of male mice, triggers the activation of thermogenic gene programs in inguinal adipocytes. Consequently, the knockout mice display higher energy expenditure and improved glucose tolerance compared to control littermates, even under high-fat diet conditions. Altogether, our findings highlight white adipocyte glutamine turnover as an important determinant of energy expenditure and metabolic health.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Metabolism |
| Vol/bind | 6 |
| Udgave nummer | 7 |
| Sider (fra-til) | 1329-1346 |
| Antal sider | 18 |
| ISSN | 2522-5812 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:Adipose tissue biopsies from cohort 2 are part of the bariatric surgery cohort followed at CRNH, Pitie-Salp\u00EAtri\u00E8re hospital (RHU-CARMMA Project), Paris, France. These samples were collected by L. Genser. We thank M. Bj\u00F6rnholm for valuable input on the animal experiments. This work was supported by grants from Margareta af Uggla\u2019s foundation (M.R.), the Swedish Research Council (M.R., N.M., A.K. and J.R.Z. including establishing grants to S.M. and L.M.), ERC-SyG SPHERES (grant no. 856404 to M.R.), the Novo Nordisk Foundation (including the Tripartite Immuno-metabolism Consortium grant no. NNF15CC0018486, the MSAM consortium grant no. NNF15SA0018346 and the MeRIAD consortium grant no. 0064142, all three to M.R., MSAM and MeRIAD to A.K. and grant no. NNF20OC0061149 to N.M.), Knut and Alice Wallenberg\u2019s Foundation (A.K., M.R., T.M. and J.R.Z., including Wallenberg Clinical Scholar to M.R.), the Center for Innovative Medicine (S.M., N.M. and M.R.), the Swedish Diabetes Foundation (M.R.), the Stockholm County Council (M.R.), the Strategic Research Program in Diabetes at Karolinska Institutet (A.K. and M.R.), the Universit\u00E9 Clermont Auvergne, Soci\u00E9t\u00E9 Francophone du Diab\u00E8te, Fondation Bettencourt Schueller (S.M.), and European Foundation for the Study of Diabetes (Rising star fellowship to S.M. and Future Leaders award to N.M.). French National Agency of Research (ANR-Captor to K.C.), Fondation pour la Recherche Medicale (grant nos. FDT201904008276, FDT202106012793 to K.C.) and Association Fran\u00E7aise d\u00B4\u00C9tude et de Recherche sur l\u00B4ob\u00E9sit\u00E9 (AFERO to S.L). L.A. and M.O.H. are supported by postdoctoral fellowship from the strategic research program in diabetes at Karolinska Institutet. S.F.C. is supported by a Novo Nordisk postdoctoral fellowship run in partnership with Karolinska Institutet. L.M. was funded by a postdoctoral grant from the Swedish Society for Medical Research.
Publisher Copyright:
© The Author(s) 2024.