We investigate the role of PPARg2 as a regulator of lipolysis and its interaction with specific genetic backgrounds as determinants of the severity of the metabolic phenotype. This question was prompted by our previous characterization of Pparg2-knockout (KO) mice that revealed striking genetic background differences in the severity of their adipose tissue development impairment and dysfunction. Analysis is done of pharmacological lipolytic responses combined with protein and mRNA expression analysis in isolated adipocytes from the gonadal pad of Pparg2-KO mice in 2 different backgrounds (129S6/SvEv and C57BL/6). We provide evidence of the prolipolytic role of PPARg2 and how these effects are modulated by genetic background, leading to differential severity of metabolic syndrome. Specifically, ablation of Pparg2 reduced both basal and stimulated lipolysis as a result of impaired β(3)-AR signaling, a general defect at downstream lipases, and increased insulin-mediated antilipolytic action. Of note, the C57BL/6 Pparg2-KO mice exhibited more active lipolytic response to catecholamines than 129S6/SvEv Pparg2-KO mice with respect to their wild-type controls. Pparg2-KO mice exhibit metabolic inflexibility resulting from the combined effects of impaired lipid deposition coupled with impaired lipolytic lipid mobilization. The genetic background-dependent differences in lipolysis may account for Pparg2-KO background-specific differences in the severity of their metabolic disturbances. Our findings identify the isoform Pparg2 as an integrator of the adipose lipid metabolism coordinating both anabolic and catabolic processes.