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

Q: What are the key findings of this study?

A high-fat diet induced significant adrenal structural changes and a steroidogenic shift in rabbits, leading to elevated 11-deoxycorticosterone levels (10.49 vs 3.16 nM) and hypertension.

Q: What is the clinical evidence from this study?

Population: Metabolic syndrome (n=43). Intervention: High-fat diet vs. Regular diet. Primary outcome: 11-deoxycorticosterone (11-DOC) levels (nM) (p=<0.001).

Q: What does this research mean for the field?

A high-fat diet induces significant structural changes and a steroidogenic shift in the adrenal glands, leading to elevated 11-deoxycorticosterone levels and hypertension independently of the renin-angiotensin system, a novel condition termed Metabolic Dysfunction-Associated Steatotic Adrenal Disease (MASAD). Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

Q: What question did this study set out to answer?

To investigate the morphological and functional alterations of the adrenal glands in a high-fat diet-induced rabbit model of metabolic syndrome.

Elena Rapizzi; Lorenzo Zanatta; Giulia Guarnieri; Serena Martinelli; Paolo Comeglio; Gabriele Acciai; Matilde Tavanti; Sandra Filippi; Letizia Canu; Annamaria Morelli; Mario Maggi

doi:10.1007/s40618-026-03033-9

August 26, 2026Journal of Endocrinological InvestigationOpen Access

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

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Key result

High-fat diet in rabbits drives ~3-fold higher 11-DOC levels and hypertension via adrenal structural changes.

P<0.001
n=43

Why the study?

Although hypertension is a hallmark of metabolic syndrome, the involvement of the adrenals remains underexplored.

Does a high-fat diet induce morpho-functional alterations of the adrenals and steroidogenic disarray in a rabbit model of metabolic syndrome?

Key Points

To investigate the morphological and functional alterations of the adrenal glands in a high-fat diet-induced rabbit model of metabolic syndrome.
Adult rabbits were fed either a regular diet or a high-fat diet (HFD) for 12 weeks.
Adrenal glands were harvested to evaluate steatosis, fibrosis, macrophage infiltration (RAM11), inflammation, and CYP21A2 expression using histology and immunohistochemistry.
Steroidogenesis and renin-angiotensin system components were characterized by tissue gene expression profiling and plasma steroid quantification via mass spectrometry.
Rabbits fed an HFD developed hypertension (mean arterial pressure 139.60 ± 27.56 vs. 85.54 ± 17.87 mmHg; p < 0.001) alongside significantly increased adrenal weight (1.350 g vs. 0.605 g; p < 0.001) and cortical fibrosis (3.93% vs. 0.044%; p = 0.002).
Circulating aldosterone was significantly lower in the HFD group (17.5 ng/dL vs. 59 ng/dL; p = 0.044), accompanied by renal renin downregulation (31.59 ± 54.5% of regular diet; p = 0.003) and suppressed adrenal CYP11B2 expression (39.16 ± 21.27% of regular diet; p = 0.009).
Plasma 11-deoxycorticosterone (10.49 nM vs. 3.16 nM; p < 0.001) and progesterone (2.40 nM vs. 0.82 nM; p = 0.002) were markedly elevated in HFD animals, with 11-deoxycorticosterone correlating positively with all metabolic syndrome features.

Structured PICO

Does a high-fat diet induce morpho-functional alterations of the adrenals and steroidogenic disarray in a rabbit model of metabolic syndrome?

P

Population

43 male New Zealand white rabbits were randomized to a high-fat diet or regular diet for 12 weeks to investigate adrenal morpho-functional alterations in metabolic syndrome.

I

Intervention

High-fat diet (regular diet supplemented with 0.5% cholesterol and 2.5% vegetable fat) for 12 weeks

C

Comparator

Regular diet for 12 weeks

O

Outcome

Morphological, histological, and immunohistochemical evaluations of adrenal glands (steatosis, inflammation, fibrosis, CYP21A2 distribution) and steroidogenesis at 12 weekssurrogate

Main Result

Absolute Event Rate: 10.49% vs 3.16%

p-value: p=<0.001

In a rabbit model, a high-fat diet induces metabolic syndrome and significant structural and functional adrenal changes (termed MASAD), potentially driving hypertension via 11-DOC accumulation independently of the RAAS.

Limitations

Unable to provide data on rabbits treated chronically with MR antagonist
Did not observe significant hypokalemia in the HFD rabbits due to hyperlipemic and haemolyzed serum
Some experiments have been performed on limited samples
Lack of determinations of circulating ACTH and renin
No a priori power calculation was performed
Limited sample size
Marked inter-individual variability in the regular diet (RD) group

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Implication

Adrenal changes in HFD-MetS rabbits may link diet to hypertension; leaves open human relevance and needs clinical studies.

Abstract

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).

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Cite This Study

Rapizzi et al. (2026) studied Metabolic syndrome (n=43). High-fat diet vs. Regular diet was evaluated on 11-deoxycorticosterone (11-DOC) levels (nM) (p=<0.001). A high-fat diet induced significant adrenal structural changes and a steroidogenic shift in rabbits, leading to elevated 11-deoxycorticosterone levels (10.49 vs 3.16 nM) and hypertension.

synapsesocial.com/papers/6a91465ad15324a1df3a9d76 https://doi.org/10.1007/s40618-026-03033-9

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

Key Points

Structured PICO

Main Result

Limitations

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Implication

Abstract

Discussion

Cite This Study

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

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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