Small Molecule-Induced Complement Factor D (Adipsin) Promotes Lipid Accumulation and Adipocyte Differentiation.
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.
Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 16419, Korea.
No-Joon
NJ
Song
Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 16419, Korea.
Suji
S
Kim
Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 16419, Korea.
Byung-Hyun
BH
Jang
Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 16419, Korea.
Seo-Hyuk
SH
Chang
Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 16419, Korea.
Ui Jeong
UJ
Yun
Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 16419, Korea.
Ki-Moon
KM
Park
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Hironori
H
Waki
Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT, 84112, United States of America.
Dean Y
DY
Li
Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, 90095, United States of America.
Peter
P
Tontonoz
Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 16419, Korea.
Kye Won
KW
Park
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002460:Cell Line; D015926:Complement C3a / Q000378:metabolism; D011416:Complement Factor D / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010080:Oxazoles / Q000494:pharmacology; D047492:Peroxisome Proliferator-Activated Receptors / Q000502:physiology; D011951:Receptors, Complement / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries; D059467:Transcriptome; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D010080:Oxazoles; D047492:Peroxisome Proliferator-Activated Receptors; D011951:Receptors, Complement; D054852:Small Molecule Libraries; C085567:complement C3a receptor; C401311:GW 7845; D014443:Tyrosine; D015926:Complement C3a; D011416:Complement Factor D