ADSF/resistin is an adipocyte specific cysteine-rich secretory factor. ADSF is not expressed in preadipocytes but its expression increases late during adipocyte differentiation of 3T3-L1 and primary preadipocytes in culture. We found that addition of ADSF inhibits adipocyte differentiation in vitro. ADSF expression is undetectable in adipose tissue of fasted animals, but increases drastically upon refeeding. ADSF mRNA level is lower in genetic or diet-induced obesity mouse models. We, therefore, hypothesize that ADSF may be a sensor for energy status of animals and function as a feedback regulator of adipogenesis. At the same time, ADSF has been identified as a TZD suppressible gene that may be responsible for insulin resistance and was named resistin. We generated transgenic mice over expressing ADSF fused to human IgGgamma, heavy chain Fc region (hFc). We found that by binding to ADSF, ADSF-hFc functions in a dominant negative manner to attenuate ADSF inhibition of adipocyte differentiation in vitro. Furthermore, the ADSF-hFc overexpressing transgenic mice are obese but show improved insulin sensitivity. The goal of this research is to elucidate the molecular mechanisms underlying the antiadipogenic action of ADSF. We will determine the specific stages of adipocyte differentiation and mode of ADSF action. We will also elucidate downstream signaling of ADSF by examining signaling pathways shown to be critical for adipocyte differentiation, using various inhibitors and dominant negative or constitutively active molecules. Next, we will identify/clone the ADSF receptor that mediates ADSF inhibition of adipogenesis. First, we will demonstrate specific high affinity binding of ADSF to a cell surface protein. We will then clone the putative ADSF receptor via mammalian expression cloning by retrovirally expressing cDNAs and fluorescence activated cell sorting. Lastly, we will examine ADSF function in vivo by generating and examining ADSF-hFc and ADSF overexpressing transgenic mice. This research is directed toward understanding adipocyte differentiation, a critical process that contributes to the development of excess adipose mass and obesity. It is important to elucidate the mechanisms of ADSF function in order to develop strategies for controlling adipogenesis as well as treating type 2 diabetes by modifying ADSF action.
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