Adipocyte metabolic state regulates glial phagocytic function

Abstract

HighlightsO_LIProlonged exposure to an obesogenic diet result in a starvation-like metabolic response in adipose tissue. C_LIO_LIObesogenic diet-induced mitochondrial lipid catabolism in adipose tissue impacts glial phagocytic function. C_LIO_LIAdipocyte ApoB is a novel regulator of glial phagocytic function. C_LIO_LILpR1, on ensheathing glia, is required for glial response to axonal injury. C_LI Obesity and type 2 diabetes are well-established risk factors for neurodegenerative disorders1-4, 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 expenditure5. Disruptions in the adipocyte-brain axis are associated with neurodegenerative conditions6, 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 microenvironment7-9. 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. O_FIG O_LINKSMALLFIG WIDTH=164 HEIGHT=200 SRC="FIGDIR/small/614765v2_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@6698e4org.highwire.dtl.DTLVardef@1bfd855org.highwire.dtl.DTLVardef@13d732org.highwire.dtl.DTLVardef@9548ff_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG