title: Novel fat depot-specific mechanisms underlie resistance to visceral obesity and inflammation in 11 β-hydroxysteroid dehydrogenase type 1-deficient mice.
abstract: OBJECTIVE
  The study objective was to determine the key early mechanisms underlying the beneficial redistribution, function, and inflammatory profile of adipose tissue in 11β-hydroxysteroid dehydrogenase type 1 knockout (11β-HSD1(-/-)) mice fed a high-fat (HF) diet.
  
  
  METHODS
  By focusing on the earliest divergence in visceral adiposity, subcutaneous and visceral fat depots from 11β-HSD1(-/-) and C57Bl/6J control mice fed an HF diet for 4 weeks were used for comparative microarray analysis of gene expression, and differences were validated with real-time PCR. Key changes in metabolic signaling pathways were confirmed using Western blotting/immunoprecipitation, and fat cell size was compared with the respective chow-fed control groups. Altered adipose inflammatory cell content and function after 4 weeks (early) and 18 weeks (chronic) of HF feeding was investigated using fluorescence (and magnetic)-activated cell sorting analysis, immunohistochemistry, and in situ hybridization.
  
  
  RESULTS
  In subcutaneous fat, HF-fed 11β-HSD1(-/-) mice showed evidence of enhanced insulin and β-adrenergic signaling associated with accretion of smaller metabolically active adipocytes. In contrast, reduced 11β-HSD1(-/-) visceral fat accumulation was characterized by maintained AMP kinase activation, not insulin sensitization, and higher adipocyte interleukin-6 release. Intracellular glucocorticoid deficiency was unexpectedly associated with suppressed inflammatory signaling and lower adipocyte monocyte chemoattractant protein-1 secretion with strikingly reduced cytotoxic T-cell and macrophage infiltration, predominantly in visceral fat.
  
  
  CONCLUSIONS
  Our data define for the first time the novel and distinct depot-specific mechanisms driving healthier fat patterning and function as a result of reduced intra-adipose glucocorticoid levels.
authors.affiliation: Endocrinology Unit, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, Scotland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wamil
authors.forename: Jenny H
authors.initials: JH
authors.lastname: Battle
authors.forename: Sophie
authors.initials: S
authors.lastname: Turban
authors.forename: Tiina
authors.initials: T
authors.lastname: Kipari
authors.forename: David
authors.initials: D
authors.lastname: Seguret
authors.forename: Ricardo
authors.initials: R
authors.lastname: de Sousa Peixoto
authors.forename: Yvonne B
authors.initials: YB
authors.lastname: Nelson
authors.forename: Dominika
authors.initials: D
authors.lastname: Nowakowska
authors.forename: David
authors.initials: D
authors.lastname: Ferenbach
authors.forename: Lynne
authors.initials: L
authors.lastname: Ramage
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hughes
authors.forename: Donald R
authors.initials: DR
authors.lastname: Dunbar
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 / Q000235:genetics / Q000378:metabolism*; D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004041:Dietary Fats / Q000009:adverse effects; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000494:pharmacology; D050152:Intra-Abdominal Fat / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D056128:Obesity, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004041:Dietary Fats; D005938:Glucocorticoids; D015850:Interleukin-6; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D055372:AMP-Activated Protein Kinases