Novel fat depot-specific mechanisms underlie resistance to visceral obesity and inflammation in 11[beta]-hydroxysteroid dehydrogenase type 1-deficient mice

OBJECTIVE--The study objective was to determine the key early mechanisms underlying the beneficial redistribution, function, and inflammatory profile of adipose tissue in 11[beta]-hydroxysteroid dehydrogenase type 1 knockout (11[beta]-[HSD1.sup.-/-]) 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 11[beta]-[HSD1.sup.-/-] and C57B1/6J 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 11[beta]-[HSD1.sup.-/-] mice showed evidence of enhanced insulin and [beta]-adrenergic signaling associated with accretion of smaller metabolically active adipocytes. In contrast, reduced 11[beta]-[HSD1.sup.-/-] 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. Diabetes 60:1158-1167, 2011