A male type-2 diabetic, treated with the peroxisome proliferator-activated receptor (PPAR) agonist, Pioglitazone, experienced exacerbation of his thyroid eye disease (TED), which had been stable and inactive for more then 2 yr. Expansion of the orbital fat developed, and we have investigated the effects of PPAR gamma agonists, including Pioglitazone and, subsequently, an antagonist on the adipogenesis of preadipocytes from TED orbits and Graves' neck fats. The percentage of differentiating cells, assessed by oil red O staining, morphological changes, and PPAR gamma transcript levels, was determined for preadipocytes in hormone/agonist-induced models of adipogenesis, supplemented or not with PPAR gamma agonists or antagonist. The PPAR gamma agonists resulted in a 2- to 13-fold increase, and a PPAR gamma antagonist produced a 2- to 7-fold reduction in adipogenesis in vitro. Effects were dose dependent and maximal at 1 or 10 micro M. We suggest that care should be exercised when selecting patients for treatment with PPAR gamma agonists and that such agonists may be contraindicated in individuals with a previous history of autoimmune thyroid or eye diseases. Our work also suggests that PPAR gamma antagonists could provide a novel therapy for TED patients in the active stage of disease.