Nuclear receptors play important roles in whole-body homeostasis controlling the expression of genes involved in several metabolic pathways in response to endogenous or exogenous compounds. Among nuclear receptors, PPARs are key players of energy, lipid and carbohydrate metabolism. Three different isoforms, a, b/d and g, each encoded by a distinct gene, have been isolated. PPARg is a master regulator of adipogenesis and is also involved in cell differentiation, insulin sensitivity and control of inflammation. Synthetic PPARg ligands, including thiazolidinediones, have been shown to increase insulin sensitivity and improve hyperglycemia. Several heterozygous loss-of-function mutations in PPARG have been described and correlated with distinct clinical phenotypes, including lipodystrophy, insulin resistance, dyslipidemia and metabolic syndrome. We have indentified a germline C to G transversion in PPARG exon 5 that causes a serine to cysteine (S289C) substitution at position 289 of the mature PPARg1 protein. The mutation bearing individuals of the investigated family have shown colonic lesions, obesity, hypercholesterolemia and hypertension as previously reported. To further elucidate the role of the S289C mutation in the overall cell metabolism, we have analyzed the expression of genes involved in lipid and glycidic metabolism. Here we report that S289C mutant significantly impairs metabolism and adipocyte differentiation in vitro.