Microglial Lipid Droplet Accumulation: A Pathological Nexus Between Obesity and Depression
Xijin Liu1, Jiacheng Chen2, Yangzhi Xie1
1Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China.
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 quantified in vivo and in vitro using 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 in vitro. 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.
Insights
High-fat diets induce depression-like behaviors by promoting lipid droplet accumulation in microglia, triggering neuroinflammation and hippocampal damage. This highlights a link between obesity, neuroinflammation, and depression.
Area of Science:
- Neuroscience
- Metabolic Disorders
- Immunology
Background:
- High-fat diets (HFD) are linked to depressive behaviors, but mechanisms are unclear.
- Microglia-mediated neuroinflammation and lipid droplet (LD) accumulation are implicated in depression.
- This study investigates microglial LDs and neuroinflammation in HFD-induced depression.
Purpose of the Study:
- To examine microglial lipid droplet accumulation in diet-induced obesity (DIO).
- To assess the role of neuroinflammation in HFD-induced depressive behaviors.
- To investigate the neurotoxic potential of microglia from DIO mice.
Main Methods:
- Compared diet-induced obese (DIO) mice with control (Con) mice.
- Assessed depressive behaviors, hippocampal damage, and microglial activation.
- Quantified microglial lipid droplets (LDs) in vivo and in vitro; performed lipidomics.
Main Results:
- DIO mice showed depressive behaviors, hippocampal damage, and neuroinflammation.
- DIO microglia exhibited increased neurotoxicity toward hippocampal neurons.
- Increased LD accumulation and altered lipid metabolism were observed in DIO microglia.
Conclusions:
- Diet-induced obesity causes depressive behaviors linked to neuroinflammation and LD accumulation in microglia.
- Lipid-laden microglia contribute to obesity-depression link via neuroinflammation.
- Lipid metabolic dysregulation in microglia is a key factor.
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