Summary
The hypothalamus is key in the control of energy balance. However, to this day strategies targeting hypothalamic neurons failed to provide viable option 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. Such 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 worsen or improves metabolic status of diet-induced obese mice. Collectively, these findings highlight a yet unappreciated role for astrocyte in the direct control of systemic metabolism and suggest potential targets for anti-obesity strategy.
Competing Interest Statement
Dr. Matthias Tschop is a member of the scientific advisory board of The LOOP Zurich Medical Research Center and the advisory board of the BIOTOPIA Naturkundemuseum Bayern. He is also a member of the board of trustees of the Max Planck Institutes of Neurobiology and Biochemistry, Martinsried, the scientific advisory board of the Max Planck Institute for Metabolism Research, Koln and a member of the advisory board of the Comprehensive Cancer Center (CCC) Munich. He was a member of the Research Cluster Advisory Panel (ReCAP) of the Novo Nordisk Foundation between 2017-2019. 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 by Novo Nordisk (2016-2020) and Sanofi-Aventis (2012-2019). He was a consultant for Bionorica SE (2013-2017), Menarini Ricerche S.p.A. (2016), Bayer Pharma AG Berlin (2016) and Bohringer Ingelheim Pharma GmbH & Co. KG (2020). He delivered a scientific lecture for Sanofi-Aventis Deutschland GmbH in 2020. As former Director of the Helmholtz Diabetes Center and the Institute for Diabetes and Obesity at Helmholtz Zentrum Munchen (2011-2018) and since 2018, as CEO of Helmholtz Zentrum Munchen, 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 Munchen as e. g. WO/2016/188932 A2 or WO/2017/194499 A1. Dr. Tschop confirms that to the best of his knowledge none of the above funding sources were involved in the preparation of this paper.