PMID- 32510471
OWN - NLM
STAT- MEDLINE
DCOM- 20210202
LR  - 20210202
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 130
IP  - 7
DP  - 2020 Jul 1
TI  - Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through 
      activation of glucocorticoid receptor.
PG  - 3791-3804
LID - 134485 [pii]
LID - 10.1172/JCI134485 [doi]
AB  - Type 2 diabetes mellitus (T2DM) has become an expanding global public health 
      problem. Although the glucocorticoid receptor (GR) is an important regulator of 
      glucose metabolism, the relationship between circulating glucocorticoids (GCs) 
      and the features of T2DM remains controversial. Here, we show that 
      17-hydroxyprogesterone (17-OHP), an intermediate steroid in the biosynthetic 
      pathway that converts cholesterol to cortisol, binds to and stimulates the 
      transcriptional activity of GR. Hepatic 17-OHP concentrations are increased in 
      diabetic mice and patients due to aberrantly increased expression of Cyp17A1. 
      Systemic administration of 17-OHP or overexpression of Cyp17A1 in the livers of 
      lean mice promoted the pathogenesis of hyperglycemia and insulin resistance, 
      whereas knockdown of Cyp17A1 abrogated metabolic disorders in obese mice. 
      Therefore, our results identify a Cyp17A1/17-OHP/GR-dependent pathway in the 
      liver that mediates obesity-induced hyperglycemia, suggesting that selectively 
      targeting hepatic Cyp17A1 may provide a therapeutic avenue for treating T2DM.
FAU - Lu, Yan
AU  - Lu Y
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
FAU - Wang, E
AU  - Wang E
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
FAU - Chen, Ying
AU  - Chen Y
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
FAU - Zhou, Bing
AU  - Zhou B
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
FAU - Zhao, Jiejie
AU  - Zhao J
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
FAU - Xiang, Liping
AU  - Xiang L
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
FAU - Qian, Yiling
AU  - Qian Y
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
FAU - Jiang, Jingjing
AU  - Jiang J
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
FAU - Zhao, Lin
AU  - Zhao L
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
FAU - Xiong, Xuelian
AU  - Xiong X
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
FAU - Lu, Zhiqiang
AU  - Lu Z
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
FAU - Wu, Duojiao
AU  - Wu D
AD  - Institute of Clinical Science, Shanghai Institute of Clinical Bioinformatics, 
      Zhongshan Hospital, Fudan University, Shanghai, China.
FAU - Liu, Bin
AU  - Liu B
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
AD  - Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of 
      Pharmacy, Jiangsu Ocean University, Lianyungang, China.
FAU - Yan, Jing
AU  - Yan J
AD  - Department of Endocrinology and Metabolism, Shanghai Jiao Tong University 
      Affiliated Sixth People's Hospital, and.
FAU - Zhang, Rong
AU  - Zhang R
AD  - Department of Endocrinology and Metabolism, Shanghai Jiao Tong University 
      Affiliated Sixth People's Hospital, and.
AD  - Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, 
      Shanghai Clinical Center for Diabetes, Shanghai, China.
FAU - Zhang, Huijie
AU  - Zhang H
AD  - Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical 
      University, Guangzhou, China.
FAU - Hu, Cheng
AU  - Hu C
AD  - Department of Endocrinology and Metabolism, Shanghai Jiao Tong University 
      Affiliated Sixth People's Hospital, and.
AD  - Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, 
      Shanghai Clinical Center for Diabetes, Shanghai, China.
AD  - Institute for Metabolic Disease, Fengxian Central Hospital, Southern Medical 
      University, Shanghai, China.
FAU - Li, Xiaoying
AU  - Li X
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and 
      Department of Endocrinology and Metabolism, and.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (NR3C1 protein, human)
RN  - 0 (NR3C1 protein, mouse)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 68-96-2 (17-alpha-Hydroxyprogesterone)
RN  - EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase)
SB  - IM
MH  - 17-alpha-Hydroxyprogesterone/*blood
MH  - Animals
MH  - Diabetes Mellitus, Experimental/blood/drug therapy
MH  - Diabetes Mellitus, Type 2/blood/drug therapy
MH  - Female
MH  - Humans
MH  - Hyperglycemia/*blood/drug therapy
MH  - Liver/*metabolism
MH  - Male
MH  - Mice
MH  - Obesity/*blood
MH  - Receptors, Glucocorticoid/*metabolism
MH  - *Signal Transduction
MH  - Steroid 17-alpha-Hydroxylase/metabolism
PMC - PMC7324200
OTO - NOTNLM
OT  - Diabetes
OT  - Endocrinology
OT  - Glucose metabolism
OT  - Metabolism
OT  - Obesity
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists.
EDAT- 2020/06/09 06:00
MHDA- 2021/02/03 06:00
PMCR- 2020/10/01
CRDT- 2020/06/09 06:00
PHST- 2019/10/23 00:00 [received]
PHST- 2020/04/08 00:00 [accepted]
PHST- 2020/06/09 06:00 [pubmed]
PHST- 2021/02/03 06:00 [medline]
PHST- 2020/06/09 06:00 [entrez]
PHST- 2020/10/01 00:00 [pmc-release]
AID - 134485 [pii]
AID - 10.1172/JCI134485 [doi]
PST - ppublish
SO  - J Clin Invest. 2020 Jul 1;130(7):3791-3804. doi: 10.1172/JCI134485.