Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

We previously reported a syndrome of severe hyperinsulinemia and early-onset hypertension in three patients with dominant-negative mutations in the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-gamma. We now report the results of further detailed pathophysiological evaluation of these subjects, the identification of affected prepubertal children within one of the original families, and the effects of thiazolidinedione therapy in two subjects. These studies 1) definitively demonstrate the presence of severe peripheral and hepatic insulin resistance in the affected subjects; 2) describe a stereotyped pattern of partial lipodystrophy associated with all the features of the metabolic syndrome and nonalcoholic steatohepatitis; 3) document abnormalities in the in vivo function of remaining adipose tissue, including the inability of subcutaneous abdominal adipose tissue to trap and store free fatty acids postprandially and the presence of very low circulating levels of adiponectin; 4) document the presence of severe hyperinsulinemia in prepubertal carriers of the proline-467-leucine (P467L) PPAR-gamma mutation; 5) provide the first direct evidence of cellular resistance to PPAR-gamma agonists in mononuclear cells derived from the patients; and 6) report on the metabolic response to thiazolidinedione therapy in two affected subjects. Although the condition is rare, the study of humans with dominant-negative mutations in PPAR-gamma can provide important insight into the roles of this nuclear receptor in human metabolism.

Original publication




Journal article



Publication Date





910 - 917


Abdomen, Adipose Tissue, Adult, Body Composition, Carrier Proteins, Fatty Acid-Binding Protein 7, Fatty Acid-Binding Proteins, Fatty Acids, Fatty Acids, Nonesterified, Fatty Liver, Female, Gene Expression, Humans, Hyperlipidemias, Insulin Resistance, Kinetics, Liver, Magnetic Resonance Imaging, Male, Metabolic Syndrome, Middle Aged, Mutation, Neoplasm Proteins, Phenotype, Receptors, Cytoplasmic and Nuclear, Rosiglitazone, Thiazoles, Thiazolidinediones, Transcription Factors, Triglycerides, Tumor Suppressor Proteins