A mechanistic link between PPARγ and the renin-angiotensin system (RAS) has been previously proposed but clinical evidence supporting the relationship is incomplete. In the current issue of Arteriosclerosis Thrombosis Vascular Biology, Caron-Debarle et al. show that four patients with familial partial lipodystrophy associated with early-onset severe hypertension (FPLD3) carry mutations in PPARγ that impair its ability to act as a ligand-activated transcription factor. Cells isolated from these patients, and cells transfected with the same mutations in PPARγ exhibit activation of the cellular RAS, increased production of reactive oxygen species and markers of inflammation, all of which are dependent upon the angiotensin-II AT1 receptor. This translational study further supports a role for PPARγ as a regulator of blood pressure through its ability to modulate the RAS.