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

Area of Science:

• Endocrinology
• Metabolism
• Inflammation

Background:

• Corticosteroid binding globulin (CBG) sequesters most circulating glucocorticoids.
• Neutrophil elastase (NE) cleaves CBG, potentially increasing local free glucocorticoid levels.
• Alpha-1-antitrypsin (AAT) inhibits NE.

Purpose of the Study:

• To investigate the role of NE and AAT in regulating local glucocorticoid bioavailability and metabolic actions.
• To explore the impact of high-fat diet (HFD) on the NE:AAT ratio in adipose tissue.
• To examine the consequences of altered NE or AAT levels on glucose homeostasis and insulin sensitivity.

Main Methods:

• Complementary studies in mice and humans.
• Manipulation of NE or AAT levels.
• High-fat diet (HFD) administration.
• Measurement of glucocorticoid levels and action in visceral adipose tissue.
• Assessment of glucose tolerance and insulin sensitivity.
• Analysis of human carriers of SERPINA1 mutations.

Main Results:

• HFD increases the NE:AAT ratio in male murine visceral adipose tissue.
• NE deficiency in HFD-fed male mice reduces local glucocorticoid action, improving glucose/insulin metabolism.
• Adrenalectomy abolishes the protective effect of NE deficiency.
• Human carriers of deleterious SERPINA1 mutations show increased adipose tissue glucocorticoid action and systemic free glucocorticoids.

Conclusions:

• NE and AAT regulate local tissue glucocorticoid bioavailability in vivo.
• A mechanism linking inflammation and metabolism via local glucocorticoid regulation is identified.
• Findings highlight potential therapeutic targets for metabolic disorders.