Inhibitor of DNA binding 2 is a small molecule-inducible modulator of peroxisome proliferator-activated receptor-gamma expression and adipocyte differentiation.
We previously identified the small molecule harmine as a regulator of peroxisome proliferator activated-receptor gamma (PPARgamma) and adipocyte differentiation. In an effort to identify signaling pathways mediating harmine's effects, we performed transcriptional profiling of 3T3-F442A preadipocytes. Inhibitor of DNA biding 2 (Id2) was identified as a gene rapidly induced by harmine but not by PPARgamma agonists. Id2 is also induced in 3T3-L1 preadipocytes treated with dexamethasone, 3-isobutyl-1-methylxanthine, and insulin, suggesting that Id2 regulation is a common feature of the adipogenic program. Stable overexpression of Id2 in preadipocytes promotes expression of PPARgamma and enhances morphological differentiation and lipid accumulation. Conversely, small interfering RNA-mediated knockdown of Id2 antagonizes adipocyte differentiation. Mice lacking Id2 expression display reduced adiposity, and embryonic fibroblasts derived from these mice exhibit reduced PPARgamma expression and a diminished capacity for adipocyte differentiation. Finally, Id2 expression is elevated in adipose tissues of obese mice and humans. These results outline a role for Id2 in the modulation of PPARgamma expression and adipogenesis and underscore the utility of adipogenic small molecules as tools to dissect adipocyte biology.
Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.
Kye Won
KW
Park
Hironori
H
Waki
Claudio J
CJ
Villanueva
Laurel A
LA
Monticelli
Cynthia
C
Hong
Sona
S
Kang
Ormond A
OA
MacDougald
Ananda W
AW
Goldrath
Peter
P
Tontonoz
D016475:3T3 Cells; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D050154:Adiposity; D000818:Animals; D002454:Cell Differentiation; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006247:Harmine / Q000494:pharmacology; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D047495:PPAR gamma / Q000235:genetics*; D034622:RNA Interference; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
C497450:ID2 protein, human; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D047495:PPAR gamma; D051153:Wnt Proteins; D006247:Harmine