Novel fat depot-specific mechanisms underlie resistance to visceral obesity and inflammation in 11 ?-hydroxysteroid dehydrogenase type 1-deficient mice.
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ABSTRACT: The study objective was to determine the key early mechanisms underlying the beneficial redistribution, function, and inflammatory profile of adipose tissue in 11?-hydroxysteroid dehydrogenase type 1 knockout (11?-HSD1(-/-)) mice fed a high-fat (HF) diet.By focusing on the earliest divergence in visceral adiposity, subcutaneous and visceral fat depots from 11?-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.In subcutaneous fat, HF-fed 11?-HSD1(-/-) mice showed evidence of enhanced insulin and ?-adrenergic signaling associated with accretion of smaller metabolically active adipocytes. In contrast, reduced 11?-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.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.
SUBMITTER: Wamil M
PROVIDER: S-EPMC3064089 | biostudies-literature | 2011 Apr
REPOSITORIES: biostudies-literature
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