title: Dietary manipulation reveals an unexpected inverse relationship between fat mass and adipose 11β-hydroxysteroid dehydrogenase type 1.
abstract: Increased dietary fat intake is associated with obesity, insulin resistance, and metabolic disease. In transgenic mice, adipose tissue-specific overexpression of the glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) exacerbates high-fat (HF) diet-induced visceral obesity and diabetes, whereas 11β-HSD1 gene knockout ameliorates this, favoring accumulation of fat in nonvisceral depots. Paradoxically, in normal mice HF diet-induced obesity (DIO) is associated with marked downregulation of adipose tissue 11β-HSD1 levels. To identify the specific dietary fats that regulate adipose 11β-HSD1 and thereby impact upon metabolic disease, we either fed mice diets enriched (45% calories as fat) in saturated (stearate), monounsaturated (oleate), or polyunsaturated (safflower oil) fats ad libitum or we pair fed them a low-fat (11%) control diet for 4 wk. Adipose and liver mass and glucocorticoid receptor and 11β-HSD1 mRNA and activity levels were determined. Stearate caused weight loss and hypoinsulinemia, partly due to malabsorption, and this markedly increased plasma corticosterone levels and adipose 11β-HSD1 activity. Oleate induced pronounced weight gain and hyperinsulinemia in association with markedly low plasma corticosterone and adipose 11β-HSD1 activity. Weight gain and hyperinsulinemia was less pronounced with safflower compared with oleate despite comparable suppression of plasma corticosterone and adipose 11β-HSD1. However, with pair feeding, safflower caused a selective reduction in visceral fat mass and relative insulin sensitization without affecting plasma corticosterone or adipose 11β-HSD1. The dynamic depot-selective relationship between adipose 11β-HSD1 and fat mass strongly implicates a dominant physiological role for local tissue glucocorticoid reactivation in fat mobilization.
authors.affiliation: Endocrinology Unit, Centre for Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Tak Yung
authors.initials: TY
authors.lastname: Man
authors.forename: Zoi
authors.initials: Z
authors.lastname: Michailidou
authors.forename: Adnan
authors.initials: A
authors.lastname: Gokcel
authors.forename: Lynne
authors.initials: L
authors.lastname: Ramage
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kenyon
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Morton
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis* / Q000235:genetics; D000273:Adipose Tissue / Q000201:enzymology* / Q000502:physiology*; D050154:Adiposity; D000818:Animals; D001823:Body Composition / Q000502:physiology*; D003345:Corticosterone / Q000378:metabolism; D004032:Diet; D004435:Eating / Q000187:drug effects; D005227:Fatty Acids / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005243:Feces / Q000737:chemistry; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015430:Weight Gain / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D011965:Receptors, Glucocorticoid; D012313:RNA; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone