Adipose tissue signaling in aldosterone-producing adenomas: paracrine and endocrine effects.

Abstract

Background: Primary aldosteronism increases the risk of cardiovascular and metabolic diseases, which might be influenced by different adipose tissue compartments. However, the interaction between the adrenal gland and different fat depots is not well understood and is the focus of this study.

Methods: We analyzed subcutaneous adipose tissue (scAT) and periadrenal adipose tissue (paAT) from patients with aldosterone-producing adenomas (APAs; included scAT, n = 11; paAT, n = 18) and, as controls, nonfunctional adrenal adenomas (NFAs; included scAT, n = 7; paAT, n = 5). A subanalysis for KCNJ5-mutated APA (diagnosed through elevated 18-oxocortisol [18-oxoF] and 18-hydroxycortisol [18-OHF]) was conducted. RNA sequencing and immunohistochemistry of AT was performed (immunohistochemistry [IHC], only on scAT). Immunohistochemistry markers included adipokines (leptin, adiponectin) and transcription factors (eg, c-jun and calmodulin-dependent protein kinase II [CaMKII]).

Results: RNA sequencing showed numerous significantly different expressed genes: APA vs NFA in scAT (68 up, 259 down), in paAT (16 up, 117 down), and in scAT vs paAT of APA patients (826 up, 1632 down). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis highlighted downregulated inflammation-associated pathways in both APA fat depots, while steroid-related pathways were upregulated especially in paAT of patients with KCNJ5 mutation, suggesting paracrine effects of aldosterone. Lipolysis-associated pathways were upregulated in the scAT of APA patients. Immunohistochemistry showed increased expression of angiotensin-converting enzyme 2 (ACE2), CaMKII, and c-jun in scAT from APA patients.

Conclusions: RNA sequencing identified significant gene expression differences in fat compartments of APA patients, implying endocrine and paracrine effects of APAs. These findings might partly explain cardiovascular consequences of primary aldosteronism and could lead to new diagnostic strategies, especially through accessible scAT.