Abstract
Original language | English |
---|---|
Pages (from-to) | 1532-1547.e6 |
Journal | Cell metabolism |
Volume | 34 |
Issue number | 10 |
DOIs | |
Publication status | Published - 4 Oct 2022 |
Keywords
- PVN
- astrocyte
- energy homeostasis
- glucose metabolism
- glutamate
- obesity
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In: Cell metabolism, Vol. 34, No. 10, 04.10.2022, p. 1532-1547.e6.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Hypothalamic astrocytes control systemic glucose metabolism and energy balance
AU - Herrera Moro Chao, Daniela
AU - Kirchner, Matthew K.
AU - Pham, Cuong
AU - Foppen, Ewout
AU - Denis, Raphael G. P.
AU - Castel, Julien
AU - Morel, Chloe
AU - Montalban, Enrica
AU - Hassouna, Rim
AU - Bui, Linh-Chi
AU - Renault, Justine
AU - Mouffle, Christine
AU - García-Cáceres, Cristina
AU - Tschöp, Matthias H.
AU - Li, Dongdong
AU - Martin, Claire
AU - Stern, Javier E.
AU - Luquet, Serge H.
N1 - Funding Information: This work was funded by the French National Research Agency/ Agence Nationale de la Recherche (ANR) grant # ANR-15-CE14-0030-01 , ANR-15-CE14-0030-02 , and ANR-15-CE14-0030-03 “Nutripathos” and the ANR-20-CE14-0025-01 “AstrObesity.” We acknowledge funding supports from the Centre National de la Recherche Scientifique (CNRS), The Université Paris Cité , and the Foundation pour la Recherche Médicale (FRM). J.E.S. was supported from National Heart, Lung, and Blood Institute Grant NIH HL090948 , National Institute of Neurological Disorders and Stroke Grant NIH NS094640 , and funding provided by the Center for Neuroinflammation and Cardiometabolic Diseases (CNCD) at Georgia State University . M.K.K. was supported from National Heart, Lung, and Blood Institute grant F32 HL158172-01 . E.M. was supported by the FRM . C.G.-C. was supported from the European Research Council (ERC) (STG grant AstroNeuroCrosstalk # 757393 ), the German Research Foundation (DFG) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198 ), and Helmholtz Excellence Network . M.H.T. was supported from ERC AdG HypoFlam , 695054 , European Research Council Executive Agency (ERCEA), DFG Excellence Cluster SyNergy EXC 2145 SyNergy – ID 390857198 , German Research Foundation (DFG), and ExNet-0041-Phase2-3 , Initiative and Networking Fund of the Helmholtz Association . We thank Giuseppe Gangarossa for scientific and technical expertise. We thank Olja Kacanski for administrative support, Isabelle Le Parco, Ludovic Maingault, Angélique Dauvin, Aurélie Djemat, Magguy Boa, and Daniel Quintas for animals’ care and Florianne Michel for genotyping. Telemetry experiments were supported by “The Continuous Glucose Telemetry Award 2018” obtained by Raphaël G.P. Denis and sponsored by Data Sciences International. We acknowledge the technical platforms Functional and Physiological Exploration (FPE) and Bioprofiler of the Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France, the viral production facility of the UMR Inserm 1089 and the animal core facility “Buffon” of the Université Paris Cité/Institut Jacques Monod. We thank the animal facility of IBPS of Sorbonne Université, Paris. Finally, we would like to thank Xuelong Mi at Virginia Tech for his critical technical support using the AQuA astrocytic calcium analysis. Funding Information: This work was funded by the French National Research Agency/Agence Nationale de la Recherche (ANR) grant # ANR-15-CE14-0030-01, ANR-15-CE14-0030-02, and ANR-15-CE14-0030-03 “Nutripathos” and the ANR-20-CE14-0025-01 “AstrObesity.” We acknowledge funding supports from the Centre National de la Recherche Scientifique(CNRS), The Université Paris Cité, and the Foundation pour la Recherche Médicale (FRM). J.E.S. was supported from National Heart, Lung, and Blood Institute Grant NIH HL090948, National Institute of Neurological Disorders and Stroke Grant NIH NS094640, and funding provided by the Center for Neuroinflammation and Cardiometabolic Diseases(CNCD) at Georgia State University. M.K.K. was supported from National Heart, Lung, and Blood Institute grant F32 HL158172-01. E.M. was supported by the FRM. C.G.-C. was supported from the European Research Council (ERC) (STG grant AstroNeuroCrosstalk # 757393), the German Research Foundation (DFG) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198), and Helmholtz Excellence Network. M.H.T. was supported from ERC AdG HypoFlam, 695054, European Research Council Executive Agency (ERCEA), DFG Excellence Cluster SyNergy EXC 2145 SyNergy – ID 390857198, German Research Foundation(DFG), and ExNet-0041-Phase2-3, Initiative and Networking Fund of the Helmholtz Association. We thank Giuseppe Gangarossa for scientific and technical expertise. We thank Olja Kacanski for administrative support, Isabelle Le Parco, Ludovic Maingault, Angélique Dauvin, Aurélie Djemat, Magguy Boa, and Daniel Quintas for animals’ care and Florianne Michel for genotyping. Telemetry experiments were supported by “The Continuous Glucose Telemetry Award 2018” obtained by Raphaël G.P. Denis and sponsored by Data Sciences International. We acknowledge the technical platforms Functional and Physiological Exploration (FPE) and Bioprofiler of the Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France, the viral production facility of the UMR Inserm 1089 and the animal core facility “Buffon” of the Université Paris Cité/Institut Jacques Monod. We thank the animal facility of IBPS of Sorbonne Université, Paris. Finally, we would like to thank Xuelong Mi at Virginia Tech for his critical technical support using the AQuA astrocytic calcium analysis. D.H.M.C. initiated and developed the project and critically participated in the overall project design. D.H.M.C. performed and M.K.K. contributed to designing research, performing experiments, analyzing data, interpreting results of experiments, preparing figures, and writing of the manuscript. C.P. E.F. R.G.P.D. J.C. C.Morel. E.M. R.H. L.-C.B. J.R. and C.Mouffle contributed to performing experiments and data analysis. C.G.-C. and M.H.T. contributed to funding and critical analysis of experimental plan and conception. D.H.M.C. D.L. C.Martin. and J.E.S. contributed to conception of the research project, writing of the manuscript, and approving the final version of the manuscript. S.H.L. supervised the whole project, secured funding, provided guidance, designed the initial experimental plan, and finalized the manuscript with the help of the co-authors. The authors declare no competing interests. Publisher Copyright: © 2022 Elsevier Inc.
PY - 2022/10/4
Y1 - 2022/10/4
N2 - The hypothalamus is key in the control of energy balance. However, strategies targeting hypothalamic neurons have failed to provide viable options to treat most metabolic diseases. Conversely, the role of astrocytes in systemic metabolic control has remained largely unexplored. Here, we show that obesity promotes anatomically restricted remodeling of hypothalamic astrocyte activity. In the paraventricular nucleus (PVN) of the hypothalamus, chemogenetic manipulation of astrocytes results in bidirectional control of neighboring neuron activity, autonomic outflow, glucose metabolism, and energy balance. This process recruits a mechanism involving the astrocytic control of ambient glutamate levels, which becomes defective in obesity. Positive or negative chemogenetic manipulation of PVN astrocyte Ca2+ signals, respectively, worsens or improves metabolic status of diet-induced obese mice. Collectively, these findings highlight a yet unappreciated role for astrocytes in the direct control of systemic metabolism and suggest potential targets for anti-obesity strategy.
AB - The hypothalamus is key in the control of energy balance. However, strategies targeting hypothalamic neurons have failed to provide viable options to treat most metabolic diseases. Conversely, the role of astrocytes in systemic metabolic control has remained largely unexplored. Here, we show that obesity promotes anatomically restricted remodeling of hypothalamic astrocyte activity. In the paraventricular nucleus (PVN) of the hypothalamus, chemogenetic manipulation of astrocytes results in bidirectional control of neighboring neuron activity, autonomic outflow, glucose metabolism, and energy balance. This process recruits a mechanism involving the astrocytic control of ambient glutamate levels, which becomes defective in obesity. Positive or negative chemogenetic manipulation of PVN astrocyte Ca2+ signals, respectively, worsens or improves metabolic status of diet-induced obese mice. Collectively, these findings highlight a yet unappreciated role for astrocytes in the direct control of systemic metabolism and suggest potential targets for anti-obesity strategy.
KW - PVN
KW - astrocyte
KW - energy homeostasis
KW - glucose metabolism
KW - glutamate
KW - obesity
UR - http://www.scopus.com/inward/record.url?scp=85139076061&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.cmet.2022.09.002
DO - https://doi.org/10.1016/j.cmet.2022.09.002
M3 - Article
C2 - 36198294
SN - 1550-4131
VL - 34
SP - 1532-1547.e6
JO - Cell metabolism
JF - Cell metabolism
IS - 10
ER -