Adipocyte GR Inhibits Healthy Adipose Expansion Through Multiple Mechanisms in Cushing Syndrome

Area of Science:

• Endocrinology
• Metabolic Diseases
• Molecular Biology

Background:

• Cushing syndrome involves excess glucocorticoids, causing metabolic issues like insulin resistance and liver steatosis.
• Adipocyte glucocorticoid receptor (GR) is implicated in vitro, but its in vivo metabolic roles in Cushing syndrome remain unclear.

Purpose of the Study:

• To investigate the in vivo roles and clinical relevance of adipocyte GR in Cushing syndrome.
• To elucidate the mechanisms by which adipocyte GR influences metabolic disturbances.

Main Methods:

• Utilized clinical samples from Cushing syndrome patients.
• Employed adipocyte-specific GR knockout (AGRKO) mice treated with corticosterone.
• Performed integrated analysis with RNA sequencing.

Main Results:

• AGRKO mice exhibited healthy adipose expansion, reduced ectopic lipid deposition, and improved insulin sensitivity.
• These metabolic improvements were linked to Atgl-mediated lipolysis via a novel glucocorticoid-responsive element.
• Analysis revealed associations between healthy adipose expansion and dysregulated tissue remodeling, preadipocyte proliferation, and circadian gene expression.

Conclusions:

• Adipocyte GR plays a crucial role in regulating adipose tissue expansion and metabolic homeostasis in Cushing syndrome.
• The findings highlight novel mechanisms involving lipolysis, tissue remodeling, and circadian rhythm regulation.
• Targeting adipocyte GR presents a potential therapeutic strategy for managing metabolic complications in Cushing syndrome.