Metabolic dysfunction-associated steatotic adrenal disease: a new entity in MetS, an experimental study in rabbits

Purpose: High-fat diets (HFDs) are major drivers of metabolic alterations (obesity, insulin resistance, and hypertension). Although hypertension is a hallmark of metabolic syndrome (MetS), the involvement of adrenals remains underexplored. This study investigates the morpho-functional alterations of the adrenals in a rabbit model of HFD-induced MetS. Methods: Adult rabbits were fed either a regular diet (RD) or a high-fat diet (HFD) for 12 weeks. Adrenal glands were harvested for subsequent analysis. Morphological, histological, and immunohistochemical evaluations were conducted to determine steatosis, inflammation, fibrosis, and CYP21A2 distribution. Steroidogenesis was analysed through gene expression profiling and by measuring plasma steroid hormones. Results: HFD rabbits developed hallmark features of MetS. The adrenals glands of HFD rabbits were larger and showed marked lipid accumulation, macrophage infiltration, inflammation, and fibrosis. Concurrent with the presence of hypertension, HFD rabbits had significantly lower aldosterone levels and systemic downregulation of renin-angiotensin system genes. Steroidogenesis was also impaired, with reduced expression of key enzymes. However, mass spectrometry showed elevated plasma levels of progesterone and 11-deoxycorticosterone (11-DOC), suggesting a steroidogenic shift. CYP21A2 enzyme expression was altered, showing reduced presence in the zona glomerulosa but increased expression in the fasciculata. Finally, 11-DOC levels correlated positively with all MetS features. Conclusion: This study reveals that HFD causes significant structural changes in the adrenal glands within a MetS model. This structural damage could lead to a steroidogenic disarray that potentially drives hypertension through the accumulation of 11-DOC, independently of RAAS. These findings identify adrenal glands as active participants in MetS pathophysiology. We termed these alterations Metabolic Dysfunction-Associated Steatotic Adrenal Disease (MASAD).