Microglial Lipid Droplet Accumulation: A Pathological Nexus Between Obesity and Depression.

Abstract

BACKGROUND: A high-fat diet (HFD) has been implicated in the induction of depressive-like behaviors, yet the underlying mechanisms remain incompletely elucidated. Growing evidence indicates that microglia-mediated neuroinflammation plays a critical role in the pathogenesis of depression, with excessive lipid droplet (LD) accumulation emerging as an early trigger for neuroinflammatory cascades. The aim of this study was to investigate microglial LD accumulation and the associated neuroinflammatory response in a model of HFD-induced depression. METHODS: Diet-induced obese (DIO) mice were compared with normal control (Con) mice. Depressive-like behaviors were evaluated through a battery of behavioral tests. Hippocampal neuronal damage and microglial activation were assessed using histological and immunofluorescence techniques. A co-culture system of glial cell-enriched isolates and hippocampal neurons was employed to evaluate the neurotoxic potential of DIO microglia. LD accumulation in microglia was quantifiedandusing Bodipy staining, Oil Red O staining, and electron microscopy. Untargeted lipidomics was performed on glial cells to characterize alterations in lipid metabolism. RESULTS: Compared with Con mice, DIO mice exhibited significant depressive-like behaviors and hippocampal neuronal damage, accompanied by enhanced microglia-mediated neuroinflammation. In the co-culture system, microglia from DIO mice demonstrated increased neurotoxicity toward hippocampal neurons. Bodipy staining and electron microscopy revealed increased accumulation of LDs in the hippocampal microglia of DIO mice. This was further confirmed in glial cells. Lipidomic profiling identified substantial disturbances in lipid metabolism in DIO microglia. CONCLUSION: Diet-induced obesity leads to depressive-like behaviors and hippocampal neuronal damage, which is associated with microglia-mediated neuroinflammation and intracellular accumulation of LDs. The enhanced neurotoxicity of DIO microglia, coupled with pronounced lipid metabolic dysregulation, suggests that lipid-laden microglia may contribute to the link between obesity and depression via neuroinflammatory mechanisms.