Complement 3a Receptor mediates high fat diet induced hypothalamic accumulation of lipid associated microglia to regulate neuroinflammation and obesity
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
- Gianluigi Veglia (ORCID: https://orcid.org/0000-0002-2795-6964)
- Seth McGonigle
- Maria Razzoli (ORCID: https://orcid.org/0000-0001-5911-4633)
- Jean Pierre Pallais (ORCID: https://orcid.org/0000-0003-1111-8031)
- Patricia R. Schrank (ORCID: https://orcid.org/0000-0001-5095-7896)
- Alessandro Bartolomucci (ORCID: https://orcid.org/0000-0001-6439-8829)
- Xavier S. Revelo (ORCID: https://orcid.org/0000-0002-2754-509X)
- Daniele Lettieri‐Barbato (ORCID: https://orcid.org/0000-0002-1172-814X)
- Michelle E. Ehrlich (ORCID: https://orcid.org/0000-0001-9397-686X)
- Alfonso Araque (ORCID: https://orcid.org/0000-0003-3840-1144)
- Hai‐Bin Ruan (ORCID: https://orcid.org/0000-0002-3858-1272)
- Audrey L. Daugherty (ORCID: https://orcid.org/0009-0005-0182-2238)
- Xuechun Chang (ORCID: https://orcid.org/0000-0002-4169-0146)
- Meenakshi Bose
- Hannah Hillman (ORCID: https://orcid.org/0009-0002-5448-3143)
- Jesse W. Williams (ORCID: https://orcid.org/0000-0003-3815-0891)
- Haiguang Wang (ORCID: https://orcid.org/0000-0001-5403-9179)
- Preethy Parthiban (ORCID: https://orcid.org/0000-0002-0132-9970)
- Pedro Rodriguez (ORCID: https://orcid.org/0000-0002-7726-8318)
- Luca Verteramo
- Stephen R. J. Salton
- Joerg Koehl
Institutions
- University of Rome Tor Vergata (IT)
- University of Minnesota (US)
- Allen Institute for Brain Science (US)
- University of Lübeck (DE)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-22
- DOI
- https://doi.org/10.64898/2026.04.18.719397
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Heart Association
- University of Minnesota
- Cure Alzheimer's Fund
- National Institutes of Health
- National Institute on Aging
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases