Complement 3a Receptor mediates high fat diet induced hypothalamic accumulation of lipid associated microglia to...

Area of Science:

• Neuroscience
• Immunology
• Metabolism

Background:

• Microglia, the brain's immune cells, play a crucial role in neurological function and disease.
• High-fat diets (HFD) induce microglial activation, leading to a lipid-associated microglial (LAM) phenotype and hypothalamic inflammation.
• The precise mechanisms regulating diet-induced microgliosis remain largely unknown.

Purpose of the Study:

• To investigate the role of Complement 3a Receptor (C3aR) in high-fat diet-induced hypothalamic gliosis and weight gain.
• To elucidate the molecular mechanisms by which C3aR influences microglial activation and lipid metabolism in obesity.

Main Methods:

• Utilized a mouse model with conditional microglial C3aR deletion.
• Administered high-fat diets and assessed physiological and molecular changes.
• Employed pharmacological antagonism of C3aR.
• Analyzed microglial phenotype, lipid droplet formation, and gene expression in the hypothalamus.

Main Results:

• HFD consumption increased microglial C3aR expression and reactive microgliosis specifically in the hypothalamus.
• Conditional deletion of microglial C3aR prevented HFD-induced hypothalamic reactive microgliosis and weight gain in male mice.
• C3aR signaling was essential for lipid-induced lipid droplet formation and the acquisition of the LAM signature.
• Pharmacological C3aR antagonism reduced HFD-induced weight gain in males but not females.

Conclusions:

• Complement 3a Receptor (C3aR) is a key mediator of diet-induced hypothalamic neuroinflammation and obesity.
• Targeting C3aR presents a potential therapeutic avenue for managing obesity and associated hypothalamic inflammation.
• C3aR's role in LAM signature acquisition highlights its importance in metabolic dysregulation.