title: Down-regulation of adipose 11beta-hydroxysteroid dehydrogenase type 1 by high-fat feeding in mice: a potential adaptive mechanism counteracting metabolic disease.
abstract: The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) amplifies intracellular glucocorticoid action in vivo. 11beta-HSD-1 activity is increased in adipose tissues of obese humans and genetically obese rodents, providing a mechanistic basis for the similarities between metabolic disease arising from high circulating glucocorticoids (Cushing's syndrome) and idiopathic obesity/metabolic syndrome where plasma glucocorticoids are typically unaltered. Fat-specific overexpression of 11beta-HSD-1 produces a metabolic syndrome in mice, whereas 11beta-HSD-1 null mice resist high-fat diet (HF)-induced visceral obesity and its metabolic consequences. Here we compared the effects of chronic (18 wk) HF feeding on adipose 11beta-HSD-1 activity in strains of mice that are either resistant (A/J) or prone (C57BL/6J) to metabolic disease. 11beta-HSD-1 activity was highest in sc fat, followed by epididymal fat, with lowest activity in the mesenteric visceral depot of both strains. 11beta-HSD-1 activity was lower in white adipose tissues of A/J compared with C57BL/6J mice. Chronic HF feeding unexpectedly caused a down-regulation of 11beta-HSD-1 in adipose tissues of both strains, despite comparable adiposity. However, A/J mice down-regulated adipose 11beta-HSD-1 to a significantly lower level than C57BL/6J mice in white and thermogenic brown adipose tissues. We propose that a lower adipose 11beta-HSD-1 set point affords a metabolic protection to A/J mice. Adaptive down-regulation of adipose 11beta-HSD-1 in response to chronic HF represents a novel mechanism that may counteract metabolic disease.
authors.affiliation: Endocrinology Unit, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, Scotland, United Kingdom. nik.morton@ed.ac.uk
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Morton
authors.forename: Lynne
authors.initials: L
authors.lastname: Ramage
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000222:Adaptation, Physiological; D000273:Adipose Tissue / Q000201:enzymology*; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage*; D015536:Down-Regulation; D004822:Epididymis; D008297:Male; D008643:Mesentery; D008659:Metabolic Diseases / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D040521:Subcutaneous Tissue; D014018:Tissue Distribution; D014781:Viscera
chemical_list: D004041:Dietary Fats; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1