An essential role for microglial Complement 3a Receptor 1 (C3aR) on high-fat diet induced hypothalamic neuroinflammation

Microglia, the resident macrophages of the central nervous system (CNS), are recognized for their integral role in brain function and diseases. In the context of high fat diet (HFD) feeding and obesity, microglia become overactive and dysfunctional, leading to maladaptive neuroinflammation, 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. Departing from the characterization of the unique expression of C3aR by microglia in the CNS, we showed that HFD leads to elevated expression of C3aR, which parallels widespread accumulation of reactive microglia in the hypothalamus and a lipid associated microglia (LAM) signature. Conditional microglial C3aR deletion protects mice from HFD-induced hypothalamic microgliosis, independent of sex and body weight gain. Mechanistically, we found that major lipid components of the HFD, namely cholesterol and oleic acid, are sufficient to increase C3aR1 expression and lipid accumulation in microglia, phenotypes that can be reversed by gene deletion or pharmacological antagonism of the receptor. Finally, the beneficial effect of C3aR silencing in microglia extends to astrocytes, preventing HFD-induced astrogliosis as well, despite these cells not expressing the complement receptor. In summary, we uncovered a previously unknown role for C3aR in diet-induced neuroinflammation and identify this receptor as a new viable candidate target to mitigate further health complications driven by gliosis. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.