Autosomal dominant familial partial lipodystrophy (FPLD) due to mutant LMNA encoding nuclear lamin A/C is characterized by adipose tissue repartitioning together with multiple metabolic disturbances, including insulin resistance and dyslipidemia. There is emerging evidence that some rare mutations in peroxisome proliferator-activated receptor-␥ (PPAR-␥), encoded by PPARG, might be associated with human lipodystrophy. We report a three-generation Canadian kindred ascertained based upon partial lipodystrophy, with a normal LMNA gene sequence. Candidate gene sequencing showed that all four affected subjects were heterozygous for a novel T3 A mutation at PPARG nucleotide 1164 in exon 5 that predicted substitution of phenylalanine at codon 388 by leucine (F388L). The mutation was absent from normal family members and normal unrelated subjects, and altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPAR-␥. The mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by a synthetic ligand. The germline transmission of a transactivation-deficient mutation in PPARG suggests that autosomal dominant partial lipodystrophy is genetically heterogeneous. Our findings are consistent with the idea that mutant PPARG can underlie the partial lipodystrophy phenotype. Diabetes 51: 3586 -3590, 2002

The antidiabetic thiazolidinediones, which include troglitazone and rosiglitazone, are ligands for the nuclear receptor peroxisome proliferator-a c t i v a t e d receptor (PPA R )-and exert their antihyperglycemic e ffects by regulation of PPA R--responsive genes. We report here that PPA R-activation by troglitazone depends on the experimental setting. Troglitazone acts as a partial agonist for PPA R-in transfected muscle (C2C12) and kidney (HEK 293T) cells, producing a submaximal transcriptional response (1.8-to 2.5-fold activation) compared with rosiglitazone (7.4-to 13-fold activation). Additionally, troglitazone antagonizes rosiglitazone-stimulated PPA R-transcriptional activity. Limited protease digestion of PPA R-suggests conformational differences in the receptor bound to troglitazone versus rosiglitazone. Consistent with this fin d i n g , an in vitro coactivator association assay demonstrated that troglitazone-bound PPA R-recruited the transcriptional coactivators p300 and steroid receptor coactivator 1 less efficiently than rosiglitazone-bound receptor. In contrast to these observations, troglitazone behaves as a full agonist of PPA R-in 3T3L1 adipocytes. Tw odimensional protein gel electrophoresis demonstrated that troglitazone and rosiglitazone regulated distinct but overlapping sets of genes in several cell types. Thus, troglitazone may behave as a partial agonist under certain physiological circumstances and as a full agonist in others. These differences could be caused by variations in the amount of specific cofactors, differences in PPA R response elements, or the presence of different isoforms of PPA R-. D i a b e t e s 4 9 :5 3 9-547, 2000 T ype 2 diabetes is characterized by decreased insulin sensitivity of peripheral tissues. Glucose homeostasis is maintained under these circumstances by increased insulin secretion from pancreatic -cells. In some cases, the -cell is unable to maintain increased output. The antidiabetic thiazolidinediones (TZDs), such as troglitazone, improve peripheral insulin sensitivity, leading to reduced blood glucose and insulin levels and the preservation of pancreatic function (1-4). Improvement of insulin sensitivity by TZDs is most likely due to the activation of the peroxisome proliferator-activated receptor (PPA R )-(5). The TZDs are high-affinity ligands for PPA R-in vitro, and the rank order of receptor affinity correlates with their in vivo hypoglycemic activity (6), with one reported exception (7). Although many of the molecular details are not clearly understood, a model has emerged in which activated PPA R-m o dulates the transcriptional activity of a set of genes encoding proteins that are important in glucose and lipid metabolism. H o w e v e r, the identity of these genes and the precise pathways leading to the normalization of insulin sensitivity remain largely unknown.R e c e n t l y, the X-ray crystal structure of the ligand-binding domain of PPA R-has been elucidated (3,8), revealing that ligand binding causes a conformational change within P PA R-such...