{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:03:26Z","timestamp":1791216206950,"version":"4.1.0"},"reference-count":37,"publisher":"American Diabetes Association","issue":"10","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,10,1]]},"abstract":"<jats:p>Peroxisome proliferator\u2013activated receptor (PPAR)\u03b3 is a key transcription factor facilitating fat deposition in adipose tissue through its proadipogenic and lipogenic actions. Human patients with dominant-negative mutations in PPAR\u03b3 display lipodystrophy and extreme insulin resistance. For this reason it was completely unexpected that mice harboring an equivalent mutation (P465L) in PPAR\u03b3 developed normal amounts of adipose tissue and were insulin sensitive. This finding raised important doubts about the interspecies translatability of PPAR\u03b3-related findings, bringing into question the relevance of other PPAR\u03b3 murine models. Here, we demonstrate that when expressed on a hyperphagic ob\/ob background, the P465L PPAR\u03b3 mutant grossly exacerbates the insulin resistance and metabolic disturbances associated with leptin deficiency, yet reduces whole-body adiposity and adipocyte size. In mouse, coexistence of the P465L PPAR\u03b3 mutation and the leptin-deficient state creates a mismatch between insufficient adipose tissue expandability and excessive energy availability, unmasking the deleterious effects of PPAR\u03b3 mutations on carbohydrate metabolism and replicating the characteristic clinical symptoms observed in human patients with dominant-negative PPAR\u03b3 mutations. Thus, adipose tissue expandability is identified as an important factor for the development of insulin resistance in the context of positive energy balance.<\/jats:p>","DOI":"10.2337\/db06-0389","type":"journal-article","created":{"date-parts":[[2006,9,26]],"date-time":"2006-09-26T19:57:52Z","timestamp":1159300672000},"page":"2669-2677","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":76,"title":["Leptin Deficiency Unmasks the Deleterious Effects of Impaired Peroxisome Proliferator\u2013Activated Receptor \u03b3 Function (P465L PPAR\u03b3) in Mice"],"prefix":"10.2337","volume":"55","author":[{"given":"Sarah L.","family":"Gray","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo Dalla","family":"Nora","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Grosse","sequence":"additional","affiliation":[{"name":"Ingenium Pharmaceuticals, Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monia","family":"Manieri","sequence":"additional","affiliation":[{"name":"Department of Normal Human Morphology, Faculty of Medicine, Ancona University, Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Stoeger","sequence":"additional","affiliation":[{"name":"GSF-National Research Center for Environment and Health, Institute of Inhalation Biology, Muenchen-Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gema","family":"Medina-Gomez","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Burling","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrid","family":"Wattler","sequence":"additional","affiliation":[{"name":"Ingenium Pharmaceuticals, Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Russ","sequence":"additional","affiliation":[{"name":"Genetics Unit, Department of Biochemistry, University of Oxford, Oxford, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giles S.H.","family":"Yeo","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V. 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