A polygenic model of the metabolic syndrome with reduced circulating and intra-adipose glucocorticoid action.
Despite major advances in understanding monogenic causes of morbid obesity, the complex genetic and environmental etiology of idiopathic metabolic syndrome remains poorly understood. One hypothesis suggests that similarities between the metabolic disease of plasma glucocorticoid excess (Cushing's syndrome) and idiopathic metabolic syndrome results from increased glucocorticoid reamplification within adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1). Indeed, 11beta-HSD-1 is now a major therapeutic target. Because much supporting evidence for a role of adipose 11beta-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 (11beta-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 11beta-HSD-1.
Morton
Nicholas M
NM
Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, UK. nik.morton@ed.ac.uk
Densmore
Valerie
V
Wamil
Malgorzata
M
Ramage
Lynne
L
Nichol
Katherine
K
Bünger
Lutz
L
Seckl
Jonathan R
JR
Kenyon
Christopher J
CJ
D000273:Adipose Tissue / Q000033:anatomy & histology / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D003433:Crosses, Genetic; D003480:Cushing Syndrome / Q000097:blood; D004822:Epididymis; D005938:Glucocorticoids / Q000097:blood*; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D051379:Mice; D008820:Mice, Obese; D008957:Models, Genetic; D009765:Obesity / Q000235:genetics / Q000473:pathology; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012867:Skin; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D005938:Glucocorticoids; D007328:Insulin; D020738:Leptin; D014280:Triglycerides; D012313:RNA; D003345:Corticosterone