High sugar diet-induced insulin resistance in glia impairs axonal clearance after injury by downregulating Draper signaling

Abstract

Obesity significantly increases the risk for developing neurodegenerative disorders, yet the precise mechanisms underlying this connection remain unclear. Defects in glial phagocytic function is a key feature of neurodegenerative disorders, as delayed clearance of neuronal debris can result in inflammation, cytotoxicity, secondary neuronal death, and poor nervous system recovery. Whether or how diet-induced obesity disrupts glial phagocytosis is unknown. Here, using a Drosophila diet-induced obesity model, we show that subjecting adult flies to a chronic high sugar diet (HSD) treatment delays the clearance of degenerating axons by causing glial insulin resistance. We find that HSD downregulates the basal and injury-induced expression of the glia-associated phagocytic receptor, Draper. Genetically inducing Insulin release from the Insulin producing cells (IPCs) phenocopies the HSD-induced Draper downregulation and insulin resistance, while attenuating insulin release from the IPCs rescues HSD-induced Draper downregulation and insulin resistance. Significantly, we show that genetically stimulating Phosphoinositide 3-kinase (PI3K), a downstream effector of Insulin receptor signaling rescues HSD-induced glial defects. Together, we provide mechanistic insights into how HSD alters glial phagocytic function in the adult brain. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.