Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability

Cristina García-Cáceres, Carmelo Quarta, Luis Varela, Yuanqing Gao, Tim Gruber, Beata Legutko, Martin Jastroch, Pia Johansson, Jovica Ninkovic, Chun Xia Yi, Ophelia Le Thuc, Klara Szigeti-Buck, Weikang Cai, Carola W. Meyer, Paul T. Pfluger, Ana M. Fernandez, Serge Luquet, Stephen C. Woods, Ignacio Torres-Alemán, C. Ronald KahnMagdalena Götz, Tamas L. Horvath, Matthias H. Tschöp

Research output: Contribution to journalArticlepeer-review

365 Scopus citations

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.

Original languageEnglish
Pages (from-to)867-880
Number of pages14
JournalCell
Volume166
Issue number4
DOIs
StatePublished - 11 Aug 2016

Keywords

  • astrocytes
  • glucose uptake
  • hypothalamus
  • insulin receptor

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