The NE/AAT/CBG axis regulates adipose tissue glucocorticoid exposure

• Published in: Nature communications 2025-01, Vol.16 (1), p.545-16, Article 545
• Main Authors: Boyle, Luke D., Miguelez-Crespo, Allende, Paul, Mhairi, Villalobos, Elisa, Toews, Julia N. C., Ivatt, Lisa, Nagy, Boglarka, Magennis, Marisa, Homer, Natalie Z. M., Andrew, Ruth, Viau, Victor, Hammond, Geoffrey L., Stimson, Roland H., Walker, Brian R., Nixon, Mark
• Format: Article
• Language: English
• Subjects: 45/77; 45/88; 45/90; 631/443/319/1557; 631/443/319/1642; 631/443/319/2723; 64/110; 82/58; Adipose tissue; Adipose Tissue - metabolism; Adult; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin - metabolism; Animals; Binding; Bioavailability; Body fat; Circulation; Diet, High-Fat; Elastase; Female; Globulins; Glucocorticoids; Glucocorticoids - metabolism; Glucose tolerance; High fat diet; Humanities and Social Sciences; Humans; Hypothalamic-pituitary-adrenal axis; Inflammation; Insulin Resistance; Intra-Abdominal Fat - metabolism; Leukocyte Elastase - genetics; Leukocyte Elastase - metabolism; Leukocytes (neutrophilic); Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; multidisciplinary; Mutation; Neutrophils; Proteolysis; Science; Science (multidisciplinary); Steroids; Transcortin - genetics; Transcortin - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-55693-x

Corticosteroid binding globulin (CBG; SERPINA6 ) binds >85% of circulating glucocorticoids but its influence on their metabolic actions is unproven. Targeted proteolytic cleavage of CBG by neutrophil elastase (NE; ELANE ) significantly reduces CBG binding affinity, potentially increasing ‘free’ glucocorticoid levels at sites of inflammation. NE is inhibited by alpha-1-antitrypsin (AAT; SERPINA1 ). Using complementary approaches in mice and humans to manipulate NE or AAT, we show high-fat diet (HFD) increases the NE:AAT ratio specifically in murine visceral adipose tissue, an effect only observed in males. Notably, HFD-fed male mice lacking NE have reduced glucocorticoid levels and action specifically in visceral adipose tissue, with improved glucose tolerance and insulin sensitivity, independent of systemic changes in free glucocorticoids. The protective effect of NE deficiency is lost when the adrenals are removed. Moreover, human asymptomatic heterozygous carriers of deleterious mutations in SERPINA1 resulting in lower AAT levels have increased adipose tissue glucocorticoid levels and action. However, in contrast to mice, humans present with systemic increases in free circulating glucocorticoid levels, an effect independent of HPA axis activation. These findings show that NE and AAT regulate local tissue glucocorticoid bioavailability in vivo, providing crucial evidence of a mechanism linking inflammation and metabolism. Corticosteroid binding globulin modulates circulating glucocorticoids, but its metabolic implications remain unclear. Here, the authors show that CBG regulators neutrophil elastase and alpha-1-antitrypsin control glucocorticoid bioavailability in adipose tissue, linking obesity and inflammation to metabolic outcomes in a sex-specific manner in mice and revealing parallels with human carriers of deleterious SERPINA1 mutations.