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Endocrine Abstracts (2017) 50 OC3.4 | DOI: 10.1530/endoabs.50.OC3.4

SFEBES2017 Oral Communications Obesity, Diabetes Thyroid (6 abstracts)

Neutrophil elastase-mediated regulation of adipose glucocorticoid exposure through CBG cleavage

Mark Nixon 1 , Lesley Hill 2 , Caroline Underhill 2 , Geoffrey Hammond 2 & Brian Walker 1

1University of Edinburgh, Edinburgh, UK; 2University of British Columbia, Vancouver, British Columbia, Canada.

Adipose exposure to glucocorticoids (GCs) results in visceral adiposity and insulin resistance. Only the unbound, free fraction of GC can diffuse into cells. Corticosteroid binding globulin (CBG) is the major GC carrier, binding 80–85% of circulating GCs with high affinity. Targeted proteolysis of CBG by neutrophil elastase (NE) significantly reduces CBG binding affinity. This suggests that neutrophil-mediated inflammation provides a regulatory mechanism for delivery of GCs to target tissues. In obesity, elevated NE activity is observed in plasma alongside adipose neutrophil infiltration. Strikingly, mice deficient in neutrophil elastase (ELA-KO) fed a high-fat diet display improved whole body insulin sensitivity and adipose insulin signaling, which we hypothesized is mediated by reduced release of GC from CBG within adipose. Male ELA-KO mice and littermate controls (8–10 weeks) were fed a high-fat diet (60% fat) for 10 weeks. Compared to controls, ELA-KO mice gained less weight, had reduced fat mass (8.1±0.9 vs 5.3±0.7 g; P=0.022), and displayed improved glucose tolerance (P=0.017, Two-way repeated measures ANOVA). Plasma CBG binding capacity, measured by ligand saturation assay, was greater in ELA-KO mice compared to controls (197±14 vs 156±12 nM; P=0.04). Despite no difference in total plasma corticosterone concentrations, mesenteric adipose corticosterone levels, measured by LC-MS/MS, were significantly reduced in ELA-KO mice compared to controls (28.6±5.9 vs 56.1±11.3 pg/mg; P=0.037). These data provide the first direct evidence that NE influences CBG binding capacity in vivo. Moreover, this is accompanied by lower GC levels in adipose tissue but not plasma, suggesting that changes in CBG binding capacity at sites of inflammation alter local tissue GC exposure by influencing the free GC fraction. This opens the possibility of NE as a therapeutic target to regulate adipose tissue GC exposure in obesity and metabolic syndrome.

Volume 50

Society for Endocrinology BES 2017

Harrogate, UK
06 Nov 2017 - 08 Nov 2017

Society for Endocrinology 

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