PPARG dysregulation as a potential molecular target in adrenal Cushing's syndrome

Area of Science:

• Endocrinology
• Molecular Biology
• Genomics

Background:

• Cushing's syndrome (CS) involves excess cortisol production.
• Endogenous CS subtypes exhibit distinct adrenal signaling pathway dysregulation.
• Identifying druggable targets is crucial for effective CS management.

Purpose of the Study:

• To perform transcriptomic analysis of adrenal signaling pathways in endogenous Cushing's syndrome.
• To identify dysregulated and potentially druggable molecular targets.
• To investigate the therapeutic potential of PPARG pathway modulation.

Main Methods:

• Next-generation sequencing of adrenal samples from patients with primary bilateral macronodular adrenal hyperplasia (PBMAH), cortisol-producing adenoma (CPA), and Cushing's disease (BADX-CD).
• Validation using quantitative PCR (QPCR) on adrenal samples and three adrenocortical cell lines (NCI-H295R, CU-ACC2, MUC1).
• In vitro studies using a PPARG activator (rosiglitazone) to assess effects on cell viability and hormone production.

Main Results:

• Pathway mapping identified the PPARG pathway as significantly downregulated in PBMAH, BADX-CD, and CPA.
• Downregulation of PPARG, FABP4, PLIN1, and ADIPOQ genes was confirmed by QPCR.
• In vitro, rosiglitazone treatment decreased cell viability and reduced aldosterone, cortisol, cortisone, and DHT production.

Conclusions:

• PPARG pathway dysregulation is implicated in endogenous Cushing's syndrome.
• PPARG activation demonstrates a therapeutic effect by reducing adrenal cell viability and hormone synthesis.
• Targeting the PPARG pathway represents a promising therapeutic strategy for endogenous hypercortisolism, independent of ACTH signaling.