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

Abstract

OBJECTIVEThe 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 METHODSBy 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.RESULTSIn 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.CONCLUSIONSOur 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.

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

“…This indicates a possible feed-forward loop-inflammation stimulating the HPA axis to secrete glucocorticoids, both of which induce C/EBP␤ in turn increasing 11␤-HSD1, further amplifying local glucocorticoid signaling and shaping the trajectory of an inflammatory response via pro-resolution macrophage polarization (600). A recent intriguing twist is added by the discovery that the C/EBP␤ posttranslational isoforms, liver inhibitory protein (LIP) and liver activator protein (LAP), play distinct physiological roles (647,763) and oppose each other in mediating 11␤-HSD1 regulation in adipose tissue by high-fat diet (190), itself linked to adipose inflammation (750).…”

How much we know about the attenuation of insulin signaling in the adipose tissue caused by glucocorticoid treatment?

“…These studies demonstrated that systemic and/or local GC excess is associated with reduced adipose tissue insulin signaling and significant glucose and lipid homeostasis imbalance [10,11,16,28] . The alterations in insulin signaling pathway include reduced adipose tissue IRS-1 Tyr and PKB Ser/Thr phosphorylation [10,11,16] . By blocking/reducing the 11β-HSD-1 enzyme activity with pharmacological [28] genetic (knockout) [11] or molecular (knockdown) [16] tools, obese mice made by prolonged GC exposure or high-fat diet become partially prevented from the glucose and lipid imbalance, suggesting a negative impact of elevated local GC abundance for adequate adipose tissue biology.…”

“…In models of visceral obesity by prolonged exposure to corticosterone [10,16] or diet-induced obesity [11,28] , it is common to observe an increase of GC availability in the visceral adipose tissue as a consequence of 11β-HSD-1 upregulation (the isoform that catalyzes the intracellular activation of GCs) [16,28] . These studies demonstrated that systemic and/or local GC excess is associated with reduced adipose tissue insulin signaling and significant glucose and lipid homeostasis imbalance [10,11,16,28] . The alterations in insulin signaling pathway include reduced adipose tissue IRS-1 Tyr and PKB Ser/Thr phosphorylation [10,11,16] .…”

“…GCs modulate several processes in the adipose tissue such as adipocyte differentiation/adipogenesis [9][10][11][12][13] , and exert both anabolic (e.g., lipogenesis) and catabolic (e.g., lipolysis) [10][11][12][13][14][15][16] functions, depending on the fat depot evaluated and stage of adipocyte differentiation/maturation. It is consensually accepted that GCs promote adipogenesis and/or lipogenesis (visceral adipose tissue) and lipolysis (subcutaneous adipose tissues), which correspond with clinical features of abdominal obesity and limited subcutaneous fat on the extremities in patients with Cushing's syndrome [4] .…”

“…The alterations in insulin signaling pathway include reduced adipose tissue IRS-1 Tyr and PKB Ser/Thr phosphorylation [10,11,16] . By blocking/reducing the 11β-HSD-1 enzyme activity with pharmacological [28] genetic (knockout) [11] or molecular (knockdown) [16] tools, obese mice made by prolonged GC exposure or high-fat diet become partially prevented from the glucose and lipid imbalance, suggesting a negative impact of elevated local GC abundance for adequate adipose tissue biology. There are similar impairments of insulin signaling in the adipose tissue in a non-obese rat model of insulin resistance made by 5-day dexamethasone administration that include increased IRS-1 Ser phosphorylation and reduced PKB Ser phosphorylation [15] .…”