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Stimulation of 3T3-L1 Adipogenesis by Signal Transducer and Activator of Transcription 5

Helix Research Institute (R.N.-W., Y. Ma., H.W.), 1532-3 Yana Kisarazu-shi Chiba, 292-0812 Japan; The Second Department of Anatomy (Y. Mo., E.S.), Wakayama Medical College, Kimiidera, Wakayama 641-0012, Japan; Department of Hematology and Oncology (I.M.), Faculty of Medicine, University of Osaka, Yamadaoka Suita-shi Osaka 565-0871, Japan; and Hubid Genome Systems Co. (M.-A.M.), Hirakawa-cho, Chiyoda-ku, Tokyo 102-0093, Japan

Address all correspondence and requests for reprints to: Hiroshi Wakao, Ph.D., Laboratory of Immune Regulation, Riken Research Center for Allergy and Immunology, c/o Department of Molecular Immunology, School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku Chiba, 260-8670 Japan. E-mail: hwakao{at}med.m.chiba-u.ac.jp.

Signal transducer and activator of transcription 5 (Stat5) mediates signaling of many cytokines and growth factors. Here we show that Stat5 functions as an initial mediator of adipogenesis. The preadipocyte cell line 3T3-L1 undergoes adipocyte differentiation upon appropriate hormonal induction. We found that Stat5A and Stat5B were strongly activated at an early stage of 3T3-L1 differentiation. To investigate physiological roles of Stat5 in adipogenesis, we have constructed 3T3-L1 cell lines in which either an exogenous wild type (wt) or dominant negative (dn) form of Stat5A expression was controlled under the doxycycline-regulatable promoter. Precocious induction of wt-Stat5A in adipocyte differentiation promoted accumulation of triglycerides within the cells. In contrast, induction of dn-Stat5A attenuated lipid accumulation. Northern blot analyses revealed that the expression of proadipogenic transcription factors was influenced in a complementary fashion by ectopic expression of either wt- or dn-Stat5A. Notably, Stat5 regulated expression of peroxisome proliferator-activated receptor-, which plays crucial roles in adipogenesis. We have also generated transgenic mice in which dn-Stat5A is expressed in an adipose tissue-specific fashion and found attenuation of peroxisome proliferator-activated receptor- and of many adipocyte-related genes. These results highlight a novel role of Stat5 in adipocyte differentiation.

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