Krox20 is a zinc finger-containing transcription factor that is abundantly expressed in adipose tissue. However, its role in fat cell differentiation has not been established. In cultured 3T3-L1 cells, Krox20 is rapidly induced by serum stimulation. Overexpression of Krox20 in both 3T3-L1 preadipocytes and multipotent NIH3T3 cells promotes adipogenesis in a hormone-dependent manner. Conversely, RNAi-mediated loss of Krox20 function reduced adipogenesis in 3T3-L1 cells. Ectopic expression of Krox20 can transactivate the C/EBPbeta promoter and increase C/EBPbeta gene expression in 3T3-L1 preadipocytes. RNAi-mediated knockdown of C/EPBbeta diminished Krox20's proadipogenic effect. Finally, coexpression of Krox20 and C/EBPbeta in naive NIH3T3 cells resulted in the pronounced induction of a fully differentiated adipocyte phenotype, an effect previously observed only with PPARgamma. These data indicate that Krox20 is necessary for adipogenesis and that, when overexpressed, Krox20 potently stimulates adipogenesis via C/EBPbeta-dependent and -independent mechanisms.

The HMGI family of proteins consists of three members, HMGIC, HMGI and HMGI(Y), that function as architectural factors and are essential components of the enhancesome. HMGIC is predominantly expressed in proliferating, undifferentiated mesenchymal cells and is not detected in adult tissues. It is disrupted and misexpressed in a number of mesenchymal tumour cell types, including fat-cell tumours (lipomas). In addition Hmgic-/- mice have a deficiency in fat tissue. To study its role in adipogenesis and obesity, we examined Hmgic expression in the adipose tissue of adult, obese mice. Mice with a partial or complete deficiency of Hmgic resisted diet-induced obesity. Disruption of Hmgic caused a reduction in the obesity induced by leptin deficiency (Lepob/Lepob) in a gene-dose-dependent manner. Our studies implicate a role for HMGIC in fat-cell proliferation, indicating that it may be an adipose-specific target for the treatment of obesity.