Glycolytically impaired glial cells fuel neural metabolism via β-oxidation

Abstract

Neuronal function is highly energy demanding and thus requires efficient and constant metabolite delivery. Like their mammalian counterparts Drosophila glia are highly glycolytic and provide lactate to fuel neuronal metabolism. However, flies are able to survive for several weeks in the absence of glial glycolysis1. Here, we study how glial cells maintain sufficient nutrient supply to neurons under conditions of carbohydrate restriction. We show that glycolytically impaired glia switch to fatty acid breakdown via β-oxidation and provide ketone bodies as an alternate neuronal fuel. Moreover, flies also rely on glial β-oxidation under starvation conditions with glial loss of β-oxidation increasing susceptibility to starvation. Further, we show that glial cells act as a metabolic sensor in the brain and can induce mobilization of peripheral energy stores to ensure brain metabolic homeostasis. In summary, our study gives pioneering evidence on the importance of glial β-oxidation and ketogenesis for brain function, and survival, under adverse conditions, like malnutrition. The glial capacity to utilize lipids as an energy source seems to be conserved from flies to humans.

Myelin lipids as nervous system energy reserves

“…Oligodendrocytes are able to generate acetoacetate from acetyl-CoA and acetoacetyl-CoA in the cholesterol pathway (by HMG-CoA lyase or direct deacylation) 32,33 . This pathway fits well recent findings in Drosophila, in which glycolytically impaired glial cells switch to beta-oxidation to support neuronal metabolism with lipidderived ketone bodies 17,34 . In mammalian brains, ketone bodies increase with age 35 and can spread horizontally like lactate through monocarboxylate transporters 36 .…”

A perspective on astrocyte regulation of neural circuit function and animal behavior

“…Recent evidence also suggests that astrocytes metabolize fatty acids via β-oxidation and that this pathway is involved in metabolic cooperation between astrocytes and neurons ( Eraso-Pichot et al., 2018 ; Fecher et al, 2019 ; Ioannou et al, 2019 ; Konttinen et al, 2019 ; Schirmeier et al, 2021 ; Timper et al, 2020 ). Furthermore, saturated lipids have been identified as a neurotoxic factor released from astrocytes under pathological conditions ( Guttenplan et al, 2021 ).…”