title: Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma.
abstract: 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.
authors.affiliation: Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: David B
authors.initials: DB
authors.lastname: Savage
authors.forename: Garry D
authors.initials: GD
authors.lastname: Tan
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Acerini
authors.forename: Susan A
authors.initials: SA
authors.lastname: Jebb
authors.forename: Maura
authors.initials: M
authors.lastname: Agostini
authors.forename: Mark
authors.initials: M
authors.lastname: Gurnell
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Williams
authors.forename: A Margot
authors.initials: AM
authors.lastname: Umpleby
authors.forename: E Louise
authors.initials: EL
authors.lastname: Thomas
authors.forename: Jimmy D
authors.initials: JD
authors.lastname: Bell
authors.forename: Adrian K
authors.initials: AK
authors.lastname: Dixon
authors.forename: Fidelma
authors.initials: F
authors.lastname: Dunne
authors.forename: Romina
authors.initials: R
authors.lastname: Boiani
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.forename: V Krishna K
authors.initials: VK
authors.lastname: Chatterjee
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
mesh_terms: D000005:Abdomen; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D001823:Body Composition; D002352:Carrier Proteins / Q000235:genetics; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D007700:Kinetics; D008099:Liver / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000627:therapeutic use; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics*; D014280:Triglycerides / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D002352:Carrier Proteins; C107608:FABP7 protein, human; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D009363:Neoplasm Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; D025521:Tumor Suppressor Proteins; D000077154:Rosiglitazone