Role of CTRP9 in obesity-associated microglial dysregulation: Promoting lipophagy via the PI3K/AKT/FOXO1 signaling...

Activation of microglia triggers neuroinflammation, which subsequently leads to neurological dysfunction, representing a significant pathological mechanism underlying obesity-related cognitive impairment. Microglial lipophagy plays a critical role in regulating lipid homeostasis and inflammation; however, its involvement in obesity-related cognitive impairment remains largely unexplored. The accumulation of lipid droplets in microglia is a prominent feature of aging and reflects an imbalance in microglial lipid metabolism. CTRP9 is an important regulator in this process. The aim of this study was to investigate the potential role of CTRP9 in high-fat diet-induced disruption of microglial lipid metabolism. First, cognitive impairment was observed in an obesity model induced by a high-fat diet. We then observed a significant increase in lipid droplets in hippocampal microglia, inhibition of autophagic activity, and decreased CTRP9 expression in obese mice with cognitive impairment. Additionally, both BV2 and HMC3 cells stimulated with palmitic acid (PA) displayed lipid droplet accumulation, along with impaired lipophagy. Mechanistically, PA stimulation significantly reduced CTRP9 expression. To further investigate the role of CTRP9, we demonstrated that silencing CTRP9 exacerbated lipophagy impairment and increased lipid droplet accumulation in microglia. Conversely, overexpression of CTRP9 was able to reverse the aberrant activation of the PI3K/AKT/FOXO1 signaling pathway in PA-stimulated BV2 cells, thereby ameliorating these phenotypes. Taken together, these results suggest that CTRP9 plays a crucial regulatory role in lipid metabolism disorders in high-fat-stimulated microglia, and its mechanism may be closely linked to the dysfunction of the PI3K/AKT/FOXO1 signaling pathway.