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Inhibitor of DNA Binding 2 Is a Small Molecule-Inducible Modulator of Peroxisome Proliferator-Activated Receptor- Expression and Adipocyte Differentiation

Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine (K.W.P., H.W., C.J.V., C.H., P.T.), University of California, Los Angeles, California 90095; Division of Biological Sciences (L.A.M., A.W.G), University of California, San Diego, La Jolla, California 92093; and Departments of Molecular and Integrative Physiology (S.K., O.M.), University of Michigan Medical Center, Ann Arbor, Michigan 48109-0622

Address all correspondence and requests for reprints to: Peter Tontonoz M.D., Ph.D., Howard Hughes Medical Institute, UCLA School of Medicine, Box 951662, Los Angeles, California 90095-1662. E-mail: ptontonoz{at}mednet.ucla.edu.

We previously identified the small molecule harmine as a regulator of peroxisome proliferator activated-receptor (PPAR) 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 PPAR 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 PPAR 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 PPAR 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 PPAR expression and adipogenesis and underscore the utility of adipogenic small molecules as tools to dissect adipocyte biology.

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Nuclear Receptors:   PPARγ

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