Astrocytes play a key role in controlling central energy and glucose homeostasis by regulating brain glucose uptake and neuronal energy supply. We previously found that a slight impairment in astrocyte mitochondrial glucose oxidation upon ablation of the glucagon like peptide (GLP)-1 receptor improves central and systemic glucose homeostasis. Thus, directly targeting astrocyte metabolism might represent a novel therapeutic strategy to improve energy and glucose homeostasis. We therefore investigated cellular and systemic metabolic effects of astrocyte-specific depletion of mitochondrial pyruvate carrier-1 (MPC-1) as a model for impaired astrocyte glucose-dependent mitochondrial oxidative phosphorylation (OXPHOS).
Postnatal, inducible astrocyte-specific MPC-1 depletion resulted in reduced body weight gain due to reduced food intake and slightly improved systemic glucose tolerance in normal control diet (NCD)-fed mice. Following 16 h fasting, NCD-fed mice with astrocyte-specific MPC-1 depletion (MPC-1ΔGFAP) showed increased mRNA expression of gluconeogenic and ketogenic markers at the level of the liver, in accordance with increased systemic ketone body levels. This suggests an amplified brain-hepatic starvation signal. In contrast, random feeding suggests an amplified brain-hepatic fed signal. In vitro studies in primary hypothalamic astrocytes demonstrated that astrocyte MPC-1 depletion resulted in impaired mitochondrial OXPHOS and compensatory increased glucose uptake in parallel with increased glycolytic actvity and enhanced endogenous fatty acid (FA) oxidation. In support of this, treatment with the FA palmitate restored the impaired OXPHOS and prevented the increase in glycolysis in MPC1 depleted astrocytes. In line with our in vitro findings, bioluminescence analysis of brain explants revealed an increased brain FA and glucose uptake in MPC-1ΔGFAP mice. Interestingly, high fat-diet feeding abolished all metabolic changes in MPC-1ΔGFAP mice.
Collectively, the results of our study uncovered a critical role of astrocyte glucose OXPHOS in central nutrient sensing and uptake in directing hepatic fasting and feeding responses.