Due to a sedentary lifestyle and an energy-dense diet the prevalence obesity rapidly increases in industrialized countries. This is a major health concern as adiposity is highly associated with major complications such as insulin resistance, type II diabetes, dyslipidemia and hypertension (components of the metabolic syndrome). Although diet and environmental intervention (i.e. caloric restriction and increased physical exercise, respectively) can prevent or delay the onset of the metabolic syndrome, this is not always sufficient and the prevalence of the metabolic syndrome keeps on rising. This underscores the importance of the development of novel therapies to treat metabolic disorders thereby reducing morbidity and mortality. Interestingly, not only an excess of fat, but also the absence of fat as found in subjects with lipodystrophy is associated with these complications. So, apparently a normal amount and/or distribution of fat are required for the maintenance of whole body metabolism. The ligand-inducible nuclear receptor Peroxisome Proliferator Activated Receptor gamma (PPARgamma) plays an important role in the differentiation, maintenance and function of adipocytes. In addition, it is the molecular target of the insulin-sensitizing thiazoledinedione (TZD) drugs. Although these TZDs were promising drugs ameliorating insulin sensitivity, some of them have already been discarded because of undesired side-effects. Nowadays, research focuses on specific PPARgamma modulators, so called SPARMs, which in theory would only exert the beneficial effects. The development of these SPARMs requires a better understanding of PPARgamma function in metabolism and its role in modulating insulin sensitivity. For this reason we studied the functional consequences of rare naturally occurring PPARgamma mutations in patients with familial partial lipodystrophy type 3 (FPLD3). FPLD3 is characterized by the loss of subcutaneous fat from the extremities and accumulation of excess fat in the intra-abdominal region and associated with metabolic complications (e.g. insulin resistance and dyslipidemia). We report a novel PPARgamma mutation (R194W) located in the DNA binding domain. As this residue contacts the phosphate backbone of DNA, disruption of this residue impaired DNA binding resulting in a transcriptionally inactive protein. In addition we showed that another FPLD3-associated PPARgamma mutation (R425C) located in the ligand binding domain affects PPARgamma function on multiple levels (e.g. ligand and DNA binding) resulting in reduced transcriptional activity. To gain more insights in the molecular mechanisms underlying the TZD effects we performed a transcriptome analysis in human mature adipocytes treated with TZDs. Using this approach we discovered two novel genes (i.e. GPR81 and RNF125) regulated by TZD-mediated PPARgamma activation. GPR81 encodes the antilipolytic G-protein-coupled receptor 81 that is exclusively expressed in adipocytes. Activation of this receptor results in the inhibition of adipocyte lipolysis. One of the beneficial effects of TZDs is a lowering of plasma free fatty acids thereby improving insulin sensitivity. We propose therefore that PPARgamma-mediated regulation of GPR81 contributes to this effect. RNF125 is an E3-ubiqituin ligase. The substrate for RNF125 in adipocytes is currently unknown and therefore the relevance of the regulation of this gene in adipocytes by TZDs needs to be further explored. In conclusion, our studies contribute to a better understanding of PPARgamma function and its role in lipid metabolism
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