RAS PROTEINS MEDIATE INDUCTION OF UNCOUPLING PROTEIN, IGF-I, AND IGF-I RECEPTOR IN RAT FETAL BROWN ADIPOCYTE CELL-LINES

Since Ras proteins are essential intermediates of some insulin-like gr owth factor I (IGF-I)/insulin signaling pathways, we examined whether Ras proteins mediate the IGF-I-induced uncoupling protein expression, Additionally, the role of Ras proteins on IGF-I and IGF-I receptor exp ression was studied, IGF-I treatment of fetal brown adipocytes cotrans fected with inducible gene constructs of SV40 large T antigen (SV40LTa g) and a transforming ras gene induced uncoupling protein expression ( UCP) in the absence of expression of the transfected genes, The expres sion of the dexamethasone-inducible transforming ras gene alone or in combination with the Zn-inducible SV40LTag mimicked the IGF-I effect i nducing UCP expression and IGF-I did not induce it further, However, t he expression of the Zn-inducible SV40LTag did not increase UCP expres sion in the absence of IGF-I. Expression of the transfected ras oncoge ne also induced IGF-I and IGF-I receptor mRNAs, whereas expression of SV40LTag did not increase them, Specific IGF-I binding was also specif ically increased by expression of the transfected ras oncogene but was not affected by expression of the SV40LTag construct, These results i ndicate that Ras proteins mediate the IGF-I-induced effect on UCP expr ession and play a role in the expression of IGF-I and IGF-I receptor. Therefore, am IGF-I autocrine/paracrine loop might be implicated in th e process of thermogenic differentiation of brown adipose tissue by a new mechanism unlike that induced by norepinephrine.