Complement 3a Receptor mediates high fat diet induced hypothalamic accumulation of lipid associated microglia to regulate neuroinflammation and obesity
Year: 2026
Type: preprint
Abstract: 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 and weight gain 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 protects mice from HFD-induced hypothalamic reactive microgliosis. C3aR deletion or pharmacological antagonism opposes HFD-induced weight gain in male but not female mice. Mechanistically, we demonstrated that C3aR is essential for lipid-induced lipid droplet formation, and acquisition of a LAM molecular signature. In summary, we uncovered a previously unknown role for C3aR in the acquisition of a LAM signature driving diet-induced gliosis, identifying this receptor as a new viable therapeutic candidate for conditions associated with hypothalamic neuroinflammation.
Authors: Jean Pierre Pallais, Maria Razzoli, Pedro Rodriguez, Seth McGonigle, Audrey Daugherty, Hannah Hillman, Luca Verteramo, Patricia R. Schrank, Preethy Parthiban, Xuechun Chang, Haiguang Wang, Gianluigi Veglia, Jörg Köhl, Meenakshi Bose, Michelle E. Ehrlich, Stephen R.J. Salton, Alfonso Araque, Daniele Lettieri Barbato, Xavier S. Revelo, Hai-Bin Ruan, Jesse W. Williams, Alessandro Bartolomucci
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: G110713544, Targeting Trem2 in Atherosclerosis Progression, G2932599285, G507384599, G5267091548, G5635228935, Minnesota Obesity Prevention Training (MnOPT), Intranasal delivery of VGF-derived peptides in a preclinical model of Alzheimer's disease, G9000187712, G9000253455, Novel directions for investigating the role of VGF in comorbid Major Depressive Disorder and Alzheimer's disease
OpenAlex ID: W7155188411