Small Molecule-Induced Complement Factor D (Adipsin) Promotes Lipid Accumulation and Adipocyte Differentiation

Area of Science:

• Cell Biology
• Metabolic Diseases
• Molecular Endocrinology

Background:

• Adipocyte differentiation is a complex process regulated by master transcription factors like Peroxisome proliferator-activated receptor γ (Pparγ).
• Identifying novel genes involved in adipogenesis is crucial for understanding metabolic health and developing therapeutic strategies.

Purpose of the Study:

• To discover novel pro-adipogenic genes using newly identified small molecules.
• To elucidate the role of complement factor D (Cfd) in adipocyte differentiation and its underlying signaling pathways.

Main Methods:

• Transcriptional profiling of preadipocytes treated with small molecules and a Pparγ agonist.
• Gene knockdown and overexpression studies using small hairpin RNA (shRNA) and standard overexpression techniques.
• Analysis of lipid accumulation and adipocyte marker gene expression.
• Investigation of complement system components, including C3a and C3a receptor (C3aR).

Main Results:

• Four genes, including Cfd and Chemokine (C-C motif) ligand 9 (Ccl9), were induced by small molecules but not by Pparγ activation.
• Cfd expression is specific to adipocytes and dysregulated in obesity.
• Cfd knockdown inhibited, while overexpression promoted, adipocyte differentiation and lipid accumulation.
• Cfd promotes adipogenesis through C3a production and C3a receptor signaling.

Conclusions:

• Complement factor D (Cfd) is a novel pro-adipogenic factor essential for adipocyte differentiation.
• Cfd exerts its effects via the C3a/C3aR signaling axis.
• Small molecule screening is a valuable approach for identifying novel regulators of adipogenesis.