Adipocyte GR inhibits healthy adipose expansion through multiple mechanisms in cushing syndrome

Reiko Hayashi, Yosuke Okuno, Kosuke Mukai, Tetsuhiro Kitamura, Tomoaki Hayakawa, Toshiharu Onodera, Masahiko Murata, Atsunori Fukuhara, Ryoichi Imamura, Yasushi Miyagawa, Norio Nonomura, Michio Otsuki, Iichiro Shimomura

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

In Cushing syndrome, excessive glucocorticoids lead to metabolic disturbances, such as insulin resistance, adipocyte hypertrophy, and liver steatosis. In vitro experiments have highlighted the importance of adipocyte glucocorticoid receptor (GR), but its metabolic roles in vivo have not been fully elucidated in Cushing syndrome. In this study, using clinical samples from patients with Cushing syndrome and adipocyte-specific GR knockout (AGRKO) mice, we investigated the roles of adipocyte GR and its clinical relevance in Cushing syndrome. Under chronic treatment with corticosterone, AGRKO mice underwent healthy adipose expansion with diminished ectopic lipid deposition and improved insulin sensitivity. These changes were associated with Atgl-mediated lipolysis through a novel intronic glucocorticoid-responsive element. Additionally, integrated analysis with RNA sequencing of AGRKO mice and clinical samples revealed that healthy adipose expansion was associated with dysregulation of tissue remodeling, preadipocyte proliferation, and expression of the circadian gene. Thus, our study revealed the roles of adipocyte GR on healthy adipose expansion and its multiple mechanisms in Cushing syndrome.

Original languageEnglish (US)
Pages (from-to)504-521
Number of pages18
JournalEndocrinology
Volume160
Issue number3
DOIs
StatePublished - Feb 14 2019

ASJC Scopus subject areas

  • Endocrinology

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