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Adaptor Protein SH2-B Linking Receptor-Tyrosine Kinase and Akt Promotes Adipocyte Differentiation by Regulating Peroxisome Proliferator-Activated Receptor Messenger Ribonucleic Acid Levels

Division of Molecular and Cellular Immunology (D.Y., N.S., T.T., H.M., R.Y., G.T., T.K., A.Y.), Medical Institute of Bioregulation and Division of Oral and Maxillofacial Oncology (D.Y., S.N.), Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan

Address all correspondence and requests for reprints to: Corresponding author: Akihiko Yoshimura, Ph.D., Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: yakihiko{at}bioreg.kyushu-u.ac.jp.

Adipocyte differentiation is regulated by insulin and IGF-I, which transmit signals by activating their receptor tyrosine kinase. SH2-B is an adaptor protein containing pleckstrin homology and Src homology 2 (SH2) domains that have been implicated in insulin and IGF-I receptor signaling. In this study, we found a strong link between SH2-B levels and adipogenesis. The fat mass and expression of adipogenic genes including peroxisome proliferator-activated receptor (PPAR) were reduced in white adipose tissue of SH2-B^–/– mice. Reduced adipocyte differentiation of SH2-B-deficient mouse embryonic fibroblasts (MEFs) was observed in response to insulin and dexamethasone, whereas retroviral SH2-B overexpression enhanced differentiation of 3T3-L1 preadipocytes to adipocytes. SH2-B overexpression enhanced mRNA level of PPAR in 3T3-L1 cells, whereas PPAR levels were reduced in SH2-B-deficient MEFs in response to insulin. SH2-B-mediated up-regulation of PPAR mRNA was blocked by a phosphatidylinositol 3-kinase inhibitor, but not by a MAPK kinase inhibitor. Insulin-induced Akt activation and the phosphorylation of forkhead transcription factor (FKHR/Foxo1), a negative regulator of PPAR transcription, were up-regulated by SH2-B overexpression, but reduced in SH2-B-deficeint MEFs. These data indicate that SH2-B is a key regulator of adipogenesis both in vivo and in vitro by regulating the insulin/IGF-I receptor-Akt-Foxo1-PPAR pathway.

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Nuclear Receptors:   PPARγ

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