To determine functional differences between the two splice variants of PPARγ (γ1 and γ2), we sought to selectively repress γ2 expression by targeting engineered zinc finger repressor proteins (ZFPs) to the γ2-specific promoter, P2. In 3T3-L1 cells, expression of ZFP55 resulted in >50% reduction in γ2 expression but had no effect on γ1, whereas adipogenesis was similarly reduced by 50%. However, ZFP54 virtually abolished both γ2 and γ1 expression, and completely blocked adipogenesis. Overexpression of exogenous γ2 in the ZFP54-expressing cells completely restored adipogenesis, whereas overexpression of γ1 had no effect. This finding clearly identifies a unique role for the PPARγ2 isoform.