Adipocyte metabolic state regulates glial phagocytic function

Summary Obesity and type 2 diabetes are well-established risk factors for neurodegenerative disorders 1–4 , yet the underlying mechanisms remain poorly understood. The adipocyte-brain axis is crucial for brain function, as adipocytes secrete signaling molecules, including lipids and adipokines, that impinge on neural circuits to regulate feeding and energy expenditure 5 . Disruptions in the adipocyte-brain axis are associated with neurodegenerative conditions 6 , but the causal links are not fully understood. Neural debris accumulates with age and injury, and glial phagocytic function is crucial for clearing this debris and maintaining a healthy brain microenvironment 7–9 . Using adult Drosophila, we investigate how adipocyte metabolism influences glial phagocytic activity in the brain. We demonstrate that a prolonged obesogenic diet increases adipocyte fatty acid oxidation and ketogenesis. Genetic manipulations that mimic obesogenic diet-induced changes in adipocyte lipid and mitochondrial metabolism unexpectedly reduce the expression of the phagocytic receptor Draper in Drosophila microglia-like cells in the brain. We identify Apolpp —the Drosophila equivalent of human apolipoprotein B (ApoB)—as a critical adipocyte-derived signal that regulates glial phagocytosis. Additionally, we show that Lipoprotein Receptor 1 (LpR1), the LDL receptor on phagocytic glia, is required for glial capacity to clear injury-induced neuronal debris. Our findings establish that adipocyte-brain lipoprotein signaling regulates glial phagocytic function, revealing a novel pathway that links adipocyte metabolic disorders with neurodegeneration. Highlights Prolonged exposure to an obesogenic diet result in a starvation-like metabolic response in adipose tissue. Obesogenic diet-induced mitochondrial lipid catabolism in adipose tissue impacts glial phagocytic function. Adipocyte ApoB is a novel regulator of glial phagocytic function. LpR1, on ensheathing glia, is required for glial response to axonal injury. Graphical abstract