Expression of the adipocyte-derived protein resistin. which is thought to play a key role in the development of insulin resistance in vivo, is regulated by a variety of hormones and mediators. including insulin and TNFalpha. Here, e describe our use of adenovirus-mediated gene transfer to determine which transcription factors and signaling pathway's affect resistin expression in 3T3-L1 adipocytes. We found that resistin expression was enhanced by overexpression of C/EBPalpha and suppressed by C/EBPzeta. a negative regulator of C/EBPalpha. Additionally, C/EBPalpha induced resistin even in L6 myoctes. Overexpression of PPARgamma markedly reduced resistin expression, whereas PPAR had no significant effect. Resistin expression was markedly suppressed by overexpression of the PI3-kinase p110alpha catalytic Subunit and by Akt. Finally. overexpression of MEK1, MKK6, or MKK7 suppressed resistin expression. These findings indicate that resistin expression is regulated by C/EBPalpha and PPARgamma, partly via modulation of signal transduction in the PI3-kinase and MAP kinase pathways. (C) 2002 Elsevier Science (USA). All rights reserved.