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Cell. 2016 Aug 11;166(4):867-880. doi: 10.1016/j.cell.2016.07.028.

Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability.

Author information

1
Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
2
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Institute of Stem Cell Research Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Physiological Genomics, Biomedical Center, Ludwigs-Maximilians-University, 80336 Munich, Germany; 7SYNERGY, Excellence Cluster Systems Neurology, Biomedical Center, Ludwigs-Maximilians-University, 80336 Munich, Germany.
4
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
5
Institute Cajal, CSIC, 28002 Madrid, Spain.
6
Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, 75205 Paris, France.
7
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, 2170 Galbraith Avenue, Cincinnati, OH 45237, USA.
8
Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany. Electronic address: tschoep@helmholtz-muenchen.de.

Abstract

We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB.

KEYWORDS:

astrocytes; glucose uptake; hypothalamus; insulin receptor

PMID:
27518562
DOI:
10.1016/j.cell.2016.07.028
[Indexed for MEDLINE]
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