ROLE OF EGF/TGF ALPHA IN ADIPOSE TISSUE DEVELOPMENT

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The inhibitory effect of epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) on early adipose tissue development will be investigated in vitro using the teratoma-derived adipogenic cell line 1246 and primary culture of newborn adipocyte precursors, and in vivo by treatment of newborn animals with EGF and by using genetically obese strains of mice. We have shown that EGF/TGF-alpha are potent inhibitors of adipose differentiation in vitro and in vivo. In the present application, we are proposing to investigate whether EGF could play an important regulatory role in the maintenance of the undifferentiated stage in adipocyte precursors in early development. Experiments are proposed 1) to determine the intracellular pathway of EGF action on adipose differentiation; 2) to investigate the TGF-alpha/EGF expression in the maintenance of undifferentiated stage in adipocytes ; 3) to study the effect of EGF/TGF-alpha on adipose tissue development in vivo in normal and obese animals; 4) to determine if abnormalities at the level of EGF (TGF-alpha) , at the level of their receptors and/or at the level of their signal transduction pathway are found in obese animals. For performing this work, we have developed an in vitro model system consisting of a teratoma-derived adipogenic cell line which differentiates in defined medium and responds to EGF and TGF-alpha, a differentiation-deficient cell line 1246-3A which produces TGF-alpha and primary culture of newborn adipocyte precursors which differentiate in defined medium and respond to EGF/TGF-alpha. Moreover, we have established an in vivo animal model system which is appropriate for investigating adipose tissue development in vivo. The study of this in vitro - in vivo model system along with the use of biochemical and molecular biology techniques is suitable for understanding the hormonal control of early adipose tissue development. This study is important since: the determination of adipocyte takes place during fetal and early post-natal life, early-onset obesity appears very quickly in human development, obesity is often associated with endocrine disorders thus suggesting a close control of adipose tissue development by hormones and growth factors.