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Because much supporting evidence for a role of adipose 11\u03b2-HSD-1 comes from transgenic or obese rodents with single-gene mutations, we investigated whether the predicted traits of metabolic syndrome and glucocorticoid metabolism were coassociated in a unique polygenic model of obesity developed by long-term selection for divergent fat mass (Fat and Lean mice with 23 vs. 4% fat as body weight, respectively). Fat mice exhibited an insulin-resistant metabolic syndrome including fatty liver and hypertension. Unexpectedly, Fat mice had a marked intra-adipose (11\u03b2-HSD-1) and plasma glucocorticoid deficiency but higher liver glucocorticoid action. Furthermore, metabolic disease was exacerbated only in Fat mice when challenged with exogenous glucocorticoids or a high-fat diet. Our data suggest that idiopathic metabolic syndrome might associate with such a novel pattern of glucocorticoid action and sensitivity in humans, with implications for tissue-specific therapeutic targeting of 11\u03b2-HSD-1.<\/jats:p>","DOI":"10.2337\/diabetes.54.12.3371","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"3371-3378","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":56,"title":["A Polygenic Model of the Metabolic Syndrome With Reduced Circulating and Intra-Adipose Glucocorticoid Action"],"prefix":"10.2337","volume":"54","author":[{"given":"Nicholas M.","family":"Morton","sequence":"first","affiliation":[{"name":"Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K"},{"name":"Animal Breeding and Development Team, Scottish Agricultural College, Penicuik, Midlothian, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Densmore","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Wamil","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynne","family":"Ramage","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Nichol","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lutz","family":"Bu\u0308nger","sequence":"additional","affiliation":[{"name":"Animal Breeding and Development Team, Scottish Agricultural College, Penicuik, Midlothian, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan R.","family":"Seckl","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Kenyon","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031209112514000_R1","doi-asserted-by":"crossref","unstructured":"Flier JS: Obesity wars: molecular progress confronts an expanding epidemic. 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