Novel Fat Depot–Specific Mechanisms Underlie Resistance to Visceral Obesity and Inflammation in 11β-Hydroxysteroid Dehydrogenase Type 1–Deficient Mice

  1. Nicholas M. Morton2
  1. 1Endocrinology Unit, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, Scotland
  2. 2Molecular Metabolism Group, Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, Scotland
  3. 3Centre for Inflammation Research, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, Scotland
  4. 4Bioinformatics Core, CVS, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, Scotland
  1. Corresponding author: Nicholas M. Morton, nik.morton{at}ed.ac.uk.
  1. M.W., J.H.B., and S.T. contributed equally to this work.

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.

RESEARCH DESIGN AND 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.

Footnotes

  • Received June 14, 2010.
  • Accepted January 20, 2011.

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  1. Diabetes vol. 60 no. 4 1158-1167
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