Abstract
Therapies based on glucagon-like peptide-1 (GLP-1) long-acting analogs and insulin are often used in the treatment of metabolic diseases. Both insulin and GLP-1 receptors are expressed in metabolically relevant brain regions, suggesting a cooperative action. However, the mechanisms underlying the synergistic actions of insulin and GLP-1R agonists remain elusive. In this study, we show that insulin-induced hypoglycemia enhances GLP-1R agonists entry in hypothalamic and area, leading to enhanced whole-body fat oxidation. Mechanistically, this phenomenon relies on the release of tanycyctic vascular endothelial growth factor A, which is selectively impaired after calorie-rich diet exposure. In humans, low blood glucose also correlates with enhanced blood-to-brain passage of insulin, suggesting that blood glucose gates the passage other energy-related signals in the brain. This study implies that the preventing hyperglycemia is important to harnessing the full benefit of GLP-1R agonist entry in the brain and action onto lipid mobilization and body weight loss.
| Original language | English |
|---|---|
| Article number | 111698 |
| Journal | Cell Reports |
| Volume | 41 |
| Issue number | 8 |
| ISSN | 2211-1247 |
| DOIs | |
| Publication status | Published - 22.11.2022 |
Funding
This work was supported by a collaborative research grant from Novo Nordisk and the Université Paris Cité. We acknowledge funding support from the Centre National la Recherche Scientifique ( CNRS ), The Université Paris Cité , the Fondation pour la Recherche Médicale ( FRM ). We thank Olja Kacanski for administrative support, Isabelle Le Parco, Ludovic Maingault, Angélique Dauvin, Aurélie Djemat, Florianne Michel, Magguy Boa, and Daniel Quintas for animal care; Sabria Allithi for genotyping; and Jeanette Bannebjerg Johansen for laboratory/technical support. W.E. thanks Massimiliano Mazzone for the Vegf lox/lox mice. We acknowledge the technical platform Functional and Physiological Exploration platform (FPE) of the Université Paris Cité, BFA, UMR 8251, CNRS, Paris, France, and the animal core facility “Buffon” of the Université Cité/Institut Jacques Monod. D.H.M.C. and R.H. received support from the National Research Agency ANR-15-CE14-0030-01 : “ Nutritpathos ” and ANR-17-CE37-0007-02 “METACOGNITION,” respectively. This work was supported by the European Research Council (ERC) Synergy grant no. 810331 to V.P. and M.S., H2020 -MSCA grant no. 748134 to M.I. The EE ANCOVA analysis done for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (MMPC, www.mmpc.org ) using their Energy Expenditure Analysis page ( http://www.mmpc.org/shared/regression.aspx ) and supported by grants DK076169 and DK115255’ . Data analysis was performed on excel XP using extracted raw value of VO2 consumed, VCO2 production (express in ml/h), and energy expenditure (Kcal/h). Subsequently, each value was expressed either by total body weight or whole lean tissue mass extracted from the EchoMRI analysis. The EE ANCOVA analysis done for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (MMPC, www.mmpc.org ) using their Energy Expenditure Analysis page ( http://www.mmpc.org/shared/regression.aspx ) and supported by grants DK076169 and DK115255’. This study was funded by Novo Nordisk, through which T.Å.P., A.S., S.L., W.F.J.H., and H.S.N. are current employees and shareholders, while C.G.S. and J.H.-S. are former employees and shareholders. The insulin and the peptide used for the experiments were provided by Novo Nordisk as well. This does not alter our adherence to all policies on sharing data and materials. All Intellectual Property Rights of the current study are owned by the Université Paris Cité, CNRS UMR 8251, and there has been no compromise of the objectivity or validity of the data in the article. C.G.S. and J.H.-S. are no longer affiliated with Novo Nordisk at the time of manuscript submission. Novo Nordisk markets liraglutide for the treatment of diabetes and obesity. No other potential conflicts of interest relevant to this article were reported. This work was supported by a collaborative research grant from Novo Nordisk and the Université Paris Cité. We acknowledge funding support from the Centre National la Recherche Scientifique (CNRS), The Université Paris Cité, the Fondation pour la Recherche Médicale (FRM). We thank Olja Kacanski for administrative support, Isabelle Le Parco, Ludovic Maingault, Angélique Dauvin, Aurélie Djemat, Florianne Michel, Magguy Boa, and Daniel Quintas for animal care; Sabria Allithi for genotyping; and Jeanette Bannebjerg Johansen for laboratory/technical support. W.E. thanks Massimiliano Mazzone for the Vegflox/lox mice. We acknowledge the technical platform Functional and Physiological Exploration platform (FPE) of the Université Paris Cité, BFA, UMR 8251, CNRS, Paris, France, and the animal core facility “Buffon” of the Université Cité/Institut Jacques Monod. D.H.M.C. and R.H. received support from the National Research Agency ANR-15-CE14-0030-01: “Nutritpathos” and ANR-17-CE37-0007-02 “METACOGNITION,” respectively. This work was supported by the European Research Council (ERC) Synergy grant no. 810331 to V.P. and M.S. H2020-MSCA grant no. 748134 to M.I. The EE ANCOVA analysis done for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (MMPC, www.mmpc.org) using their Energy Expenditure Analysis page (http://www.mmpc.org/shared/regression.aspx) and supported by grants DK076169 and DK115255’. W.B. initiated the project, conducted most experiments, and provided guidance throughout the project. C.G.S. S. Luquet, W.F.J.H. H.S.N. A.S. J.H.-S. and T.Å.P. conducted imaging experiments, synthetized fluorescent compounds, and provided expertise on analysis. M.I. provided critical input and experiment throughout the project in the whole revision part. D.H.M.C. R.H. C. Morel, C. Martin, C. Meresse, G.G. R.G.P.D. and J.C. carried out metabolic and behavioral phenotyping. A.P. M.H. and W.M. conducted the experiments in humans. M.I. M.D. M.S. and V.P. provided expertise and animal models to explore tanycytic function. C. Martin, G.G. M.I. and V.P. provided critical insight for manuscript preparation. W.B. M.I. G.G. C. Martin, M.I. V.P. and S. Luquet designed and planned the experiments. S. Luquet designed and supervised the whole project, secured funding, and wrote the manuscript with the help of all co-authors. This study was funded by Novo Nordisk, through which T.Å.P. A.S. S.L. W.F.J.H. and H.S.N. are current employees and shareholders, while C.G.S. and J.H.-S. are former employees and shareholders. The insulin and the peptide used for the experiments were provided by Novo Nordisk as well. This does not alter our adherence to all policies on sharing data and materials. All Intellectual Property Rights of the current study are owned by the Université Paris Cité, CNRS UMR 8251, and there has been no compromise of the objectivity or validity of the data in the article. C.G.S. and J.H.-S. are no longer affiliated with Novo Nordisk at the time of manuscript submission. Novo Nordisk markets liraglutide for the treatment of diabetes and obesity. No other potential conflicts of interest relevant to this article were reported.
