Inhibition of adipocyte differentiation by resistin-like molecule α: Biochemical characterization of its oligomeric nature

A novel family of cysteine-rich secreted proteins with unique tissue distribution has recently been identified. One of the members, resistin (for "resistance to insulin"), also called FIZZ3, was identified in a screen for molecules that are down-regulated in mature adipocytes upon administration of thiazolidinediones. The prototypical member of this family was originally identified from bronchoalveolar lavage fluid of inflamed lungs and designated FIZZ1 ("found in inflammatory zone"). This molecule was also found to be highly expressed in adipose tissue and was named resistin-like molecule α (RELMα). Here we demonstrate that RELMα inhibits the differentiation of 3T3-L1 preadipocytes into adipocytes. RELMα has no effect on proliferation of 3T3-L1 preadipocytes. Pretreatment of 3T3-L1 preadipocytes with RELMα does not affect insulin- or platelet-derived growth factor-induced mitogenesis. IRS-1 phosphorylation and glucose transport stimulated by insulin in mature adipocytes were also unaffected by RELMα. We show that RELMα forms disulfide-linked homooligomers based on results from electrophoresis under reducing and nonreducing conditions, coimmunoprecipitation experiments as well as by mass spectrometry. In addition, RELMα is able to form heterooligomers with resistin but not RELMβ. Since RELMα is expressed by adipose tissue and it is a secreted factor, our findings suggest that RELMα may be involved in the control of the adipogenesis as well as in the process of muscle differentiation.