Recent research has unveiled the complex relationship between the NE/AAT/CBG axis and glucocorticoid exposure within adipose tissue, fundamentally linking inflammation to metabolic processes. This connection is especially significant as glucocorticoids, produced by the adrenal glands, play an integral role in mediATING the body’s response to stress and regulating fuel metabolism.
Glucocorticoids, such as cortisol, are primarily transported by corticosteroid binding globulin (CBG), which binds approximately 85% of these hormones, rendering them inactive. The study focuses on the influence of neutrophil elastase (NE)—an enzyme linked to inflammatory responses—and alpha-1 antitrypsin (AAT), its inhibitor, on altering this regulation.
Utilizing genetic models and targeted dietary interventions, researchers demonstrated how the high-fat diet (HFD) impacts the NE:AAT ratio within visceral adipose tissue, predominantly among male mice. Notably, male mice lacking NE exhibited reduced levels of glucocorticoids and improved insulin sensitivity, pointing to NE's significant role as the gatekeeper of glucocorticoid activity under high-fat conditions.
Conversely, the study also identified notable differences when looking at human subjects, particularly asymptomatic carriers of mutations causing lower AAT levels. These individuals displayed heightened levels of free glucocorticoids, indicating systemic changes unique to humans, contrasting the findings from animal models. The researchers stated, "These findings establish a physiological role for the NE/AAT/CBG axis in regulating glucocorticoid action, linking inflammation with adverse metabolism."
Through laboratory experiments, it was confirmed how NE cleaves CBG, leading to reduced binding capacity and, as such, increases the free glucocorticoid fraction available to tissues. These processes have far-reaching consequences, especially concerning metabolic disorders like insulin resistance, which is often exacerbated by elevated glucocorticoid levels.
Previous studies have suggested heightened immunological responses within adipose tissue during obesity; classes of immune cells, including neutrophils, infiltrate this tissue significantly. Alongside, the results from the study highlight how the presence of NE leads to enhanced local glucocorticoid bioavailability, thereby continuing the cycles of metabolic dysfunction.
The reverse scenario was observed with mouse models lacking NE, which indicated clearer benefits such as improved glucose tolerance and reduced weight gain when subjected to the HFD. Despite these benefits, the study drew attention to the necessity of adrenal influence; eliminating adrenal glands nullified the protective effects, showcasing the interdependence of these biological systems.
On translating these mouse model findings to human physiology, the study's exploration of AAT-deficient subjects showcases rising systemic free cortisol levels. Here, the team noted, "High-fat diet increased the NE:AAT ratio, significantly impacting glucocorticoid levels and insulin sensitivity.” Remarkably, this systemic release remains unexplained since it was seemingly unaffected by central HPA axis activation.
The broader implication of this research lies not just within academic circles but within potential therapeutic avenues targeting the NE/AAT/CBG axis via pharmacological methods to mitigate adverse metabolic effects associated with stress responses. The researchers call attention to targeting this regulatory mechanism as it may present new strategies to combat metabolic syndromes linked with inflammation.
Overall, evidence from this comprehensive study provides substantial insight, affirming the need for future research focused on dissecting hormonal interactions at the local tissue level and their systemic repercussions, emphasizing the significant role of inflammatory mediators like NE within metabolic networks. The study concludes with hopes of paving pathways to potential treatments aimed at regulating these pathways and improving overall metabolic health.