Journal Article

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

Chang, Seo-Hyuk, Park, Ki-Moon, Li, Dean Y., Tontonoz, Peter, Yun, Ui Jeong, Waki, Hironori, Kim, Suji, Jang, Byung-Hyun, Song, No-Joon, Park, Kye Won

2016

Overview

Adipocytes are differentiated by various transcriptional cascades integrated on the master regulator, Pparγ. To discover new genes involved in adipocyte differentiation, preadipocytes were treated with three newly identified pro-adipogenic small molecules and GW7845 (a Pparγ agonist) for 24 hours and transcriptional profiling was analyzed. Four genes, Peroxisome proliferator-activated receptor γ (Pparγ), human complement factor D homolog (Cfd), Chemokine (C-C motif) ligand 9 (Ccl9), and GIPC PDZ Domain Containing Family Member 2 (Gipc2) were induced by at least two different small molecules but not by GW7845. Cfd and Ccl9 expressions were specific to adipocytes and they were altered in obese mice. Small hairpin RNA (shRNA) mediated knockdown of Cfd in preadipocytes inhibited lipid accumulation and expression of adipocyte markers during adipocyte differentiation. Overexpression of Cfd promoted adipocyte differentiation, increased C3a production, and led to induction of C3a receptor (C3aR) target gene expression. Similarly, treatments with C3a or C3aR agonist (C4494) also promoted adipogenesis. C3aR knockdown suppressed adipogenesis and impaired the pro-adipogenic effects of Cfd, further suggesting the necessity for C3aR signaling in Cfd-mediated pro-adipogenic axis. Together, these data show the action of Cfd in adipogenesis and underscore the application of small molecules to identify genes in adipocytes.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Accumulation / Adipocytes / Adipocytes - cytology / Adipocytes - drug effects / Adipogenesis / Adipogenesis - drug effects / Adipogenesis - genetics / Adipogenesis - physiology / Animals / Antibiotics / Biology / Biology and Life Sciences / Biotechnology / Cascades / Cell Line / Complement C3a - metabolism / Complement component C3a / Complement factor D / Complement Factor D - physiology / Complement receptors / Data processing / Diabetes / Differentiation / Fibroblasts / Food science / Gene expression / Genes / Genetic aspects / HEK293 Cells / Homology / Humans / Identification / Insulin / Ligands / Male / Medicine / Medicine and Health Sciences / Metabolic disorders / Mice / Mice, Inbred C57BL / Obesity / Oxazoles - pharmacology / Peroxisome Proliferator-Activated Receptors - physiology / Phosphorylation / Physical Sciences / Preadipocytes / Proteins / Receptors, Complement - metabolism / Ribonucleic acid / RNA / Signal Transduction / Signaling / Small Molecule Libraries / Studies / Transcription / Transcription (Genetics) / Transcriptome / Tyrosine - analogs & derivatives / Tyrosine - pharmacology