A better understanding of the mechanisms underlying obesity and its comorbidities is key to designing new therapies and treatments. PPARγ is a master regulator of adipocyte biology but the functions of its isoforms are poorly distinguished. Here we demonstrated that PPARγ1 is preferentially expressed in catabolic fat depots while PPARγ2 presents itself at a higher level in browning-resistant depots. PPARγ2, but not PPARγ1, responds to endogenous ligands to induce adipogenesis, and the isoforms regulate distinct sets of white and brown adipocyte genes. Moreover, PPARγ1 negatively correlates while PPARγ2 positively correlates with adiposity in human subcutaneous and visceral fat. These results together indicate that PPARγ1 and PPARγ2 have distinct functions in regulating adipocyte plasticity, and future research should take into account the binary roles of both isoforms in order to identify druggable gene targets and pathways relevant for treatment of metabolic disorders.