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

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’ g...

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Vydané v:Nature communications Ročník 16; číslo 1; s. 545 - 16
Hlavní autori: 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
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: London Nature Publishing Group UK 09.01.2025
Nature Publishing Group
Nature Portfolio
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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
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Shrnutí: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.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-55693-x