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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-\u03b3 mutation; 5) provide the first direct evidence of cellular resistance to PPAR-\u03b3 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-\u03b3 can provide important insight into the roles of this nuclear receptor in human metabolism.<\/jats:p>","DOI":"10.2337\/diabetes.52.4.910","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"910-917","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":372,"title":["Human Metabolic Syndrome Resulting From Dominant-Negative Mutations in the Nuclear Receptor Peroxisome Proliferator-Activated Receptor-\u03b3"],"prefix":"10.2337","volume":"52","author":[{"given":"David B.","family":"Savage","sequence":"first","affiliation":[{"name":"Department of Medicine, Addenbrooke\u2019s Hospital, Cambridge, U.K"},{"name":"Department of Clinical Biochemistry, Addenbrooke\u2019s Hospital, Cambridge, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garry D.","family":"Tan","sequence":"additional","affiliation":[{"name":"Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Infirmary, Oxford, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo L.","family":"Acerini","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Addenbrooke\u2019s Hospital, Cambridge, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan A.","family":"Jebb","sequence":"additional","affiliation":[{"name":"Medical Research Council Human Nutrition Research, Cambridge, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Agostini","sequence":"additional","affiliation":[{"name":"Department of Medicine, Addenbrooke\u2019s Hospital, Cambridge, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Gurnell","sequence":"additional","affiliation":[{"name":"Department of Medicine, Addenbrooke\u2019s Hospital, Cambridge, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel L.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Addenbrooke\u2019s Hospital, Cambridge, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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