Single-cell RNA sequencing uncovers molecular features underlying microglial lipid accumulation and depression-related behaviors in high-fat diet mouse model of obesity

Obesity is a worldwide health crisis, with unhealthy diet as a major contributor. Comorbid neuropsychiatric conditions such as depression and anxiety are associated with obesity. Since obesity is a pro-inflammatory state, chronic neuroinflammation may mediate obesity and neuropsychiatric comorbidity. We used RNA-seq to provide a single-cell resolution transcriptome of brain immune cells using long-term high-fat diet (HFD) to model obesity in male mice. HFD mice exhibited depression and anxiety-like behavior. We observed a shift towards increased proportions of lipid droplet-accumulating microglia (LDAM) in the long-term HFD brain. By in-depth characterization of the transcriptional signature of LDAM, we identified that ACSL1, a key regulator of lipid droplet biogenesis, was highly expressed in LDAM induced by HFD. Finally, we demonstrated that ACSL1 inhibition reduced lipid droplets deposition in microglia exposed to free fatty acids (FFA). Our findings provide a comprehensive view of the molecular changes in brain immune cells associated with HFD, suggesting a link between microglial lipid droplet accumulation and neurological comorbidities induced by obesity.