TY - JOUR
T1 - Adipocyte GR inhibits healthy adipose expansion through multiple mechanisms in cushing syndrome
AU - Hayashi, Reiko
AU - Okuno, Yosuke
AU - Mukai, Kosuke
AU - Kitamura, Tetsuhiro
AU - Hayakawa, Tomoaki
AU - Onodera, Toshiharu
AU - Murata, Masahiko
AU - Fukuhara, Atsunori
AU - Imamura, Ryoichi
AU - Miyagawa, Yasushi
AU - Nonomura, Norio
AU - Otsuki, Michio
AU - Shimomura, Iichiro
N1 - Funding Information:
Financial Support: This work was supported by Health Labor Sciences Research Grant Nanchitou (Nan)-Ippan-046 from the Ministry of Health, Labor, and Welfare, Japan.
Publisher Copyright:
© 2019 Endocrine Society.
PY - 2019/2/14
Y1 - 2019/2/14
N2 - 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.
AB - 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.
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U2 - 10.1210/en.2018-01029
DO - 10.1210/en.2018-01029
M3 - Article
C2 - 30649271
AN - SCOPUS:85061483553
SN - 0013-7227
VL - 160
SP - 504
EP - 521
JO - Endocrinology
JF - Endocrinology
IS - 3
ER -