Adipocyte-specific modulation of 11β-HSD enzymes for the treatment of obesity in male mice.

Glucocorticoids (GCs) are potent regulators of energy balance and adipose tissue function, making them attractive targets for obesity treatments. The local activation and inactivation of GCs are mediated by two key enzymes: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates active GCs, and type 2 (11β-HSD2), which inactivates them. In this study, we explored the therapeutic potential of modulating adipose GC metabolism by targeting 11β-HSD enzymes using adeno-associated virus (AAV)-based gene delivery systems. Specifically, we used AAV-double floxed inverted orientation (DIO)-mediated overexpression of 11β-HSD2 and CRISPR-Cas9-mediated knockout of 11β-HSD1 in adipocytes. Adipocyte-specific overexpression of 11β-HSD2 suppressed GC-responsive gene expression but did not prevent diet-induced obesity, enhance thermogenic capacity under cold exposure, or improve GC-driven metabolic dysfunction. In contrast, adipocyte-specific deletion of 11β-HSD1 reduced adiposity and ameliorated hepatic steatosis in high-fat diet-fed male mice. However, these metabolic benefits were not observed in female mice, indicating a possible sex-specific response to adipose GC modulation. These findings suggest that although 11β-HSD2 overexpression alone is insufficient to counteract GC-related metabolic dysfunction, inhibition of 11β-HSD1 may offer modest metabolic benefits in males. Overall, this study highlights the sex-dependent roles of 11β-HSD isoenzymes in adipose GC regulation and their therapeutic potential in obesity.NEW & NOTEWORTHY This study used advanced AAV-based strategies to modulate GC activity specifically in adipose tissues. Adipocyte-specific overexpression of 11β-HSD2 via AAV-DIO delivery did not mitigate the metabolic phenotypes in mice with excess GCs or obesity. In contrast, inducible knockout of 11β-HSD1 in adipocytes improved high-fat diet-induced adiposity and hepatic steatosis. These findings provide an additional understanding of 11β-HSD activity in adipose tissues.