Complement 3a receptor mediates high fat diet induced hypothalamic accumulation of lipid associated microglia to regulate neuroinflammation

Microglia, the resident macrophages of the central nervous system, are recognized for their heterogeneity and integral role in brain function and diseases. In the context of high fat diet (HFD) feeding and obesity, microglia become overactive, acquiring a prevailing lipid associated microglial phenotype (also known as LAM). Yet, how microgliosis is induced and regulated remains unclear. Here we report a key role for the Complement 3a Receptor (C3aR) on HFD-induced hypothalamic gliosis in mice. HFD consumption leads to elevated microglial expression of C3aR, which parallels widespread accumulation of reactive microglia, selectively in the hypothalamus. Conditional microglial C3aR deletion or pharmacological antagonism protects mice from HFD-induced hypothalamic reactive microgliosis. C3aR deletion or pharmacological antagonism opposes HFD-induced weight gain in male mice. Mechanistically, we demonstrated that C3aR is essential for lipid-induced lipid droplet formation. We also showed that C3aR deletion attenuates HFD-induced LAM transcriptional remodeling in vivo. In summary, we uncovered a previously unknown role for C3aR in the induction of a LAM signature driving diet-induced gliosis, identifying this receptor as a new viable therapeutic candidate for conditions associated with hypothalamic neuroinflammation.