Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor
Yan Lu, … , Cheng Hu, Xiaoying Li
Yan Lu, … , Cheng Hu, Xiaoying Li
Published June 8, 2020
Citation Information: J Clin Invest. 2020;130(7):3791-3804. https://doi.org/10.1172/JCI134485.
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Research Article Endocrinology Metabolism

Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor

Abstract

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.

Authors

Yan Lu, E Wang, Ying Chen, Bing Zhou, Jiejie Zhao, Liping Xiang, Yiling Qian, Jingjing Jiang, Lin Zhao, Xuelian Xiong, Zhiqiang Lu, Duojiao Wu, Bin Liu, Jing Yan, Rong Zhang, Huijie Zhang, Cheng Hu, Xiaoying Li

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Figure 3

Increased Cyp17A1 expression in obese livers.

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Increased Cyp17A1 expression in obese livers. (A) Relative mRNA levels o...
(A) Relative mRNA levels of Cyp17A1 in the liver, testis, iWATs, adrenal gland, brain, and pituitary gland of mice fed an HFD or an NCD for 12 weeks. n = 6 per group. (B) Western blots of total liver lysates from mice fed NCD or HFD diet. (C) Relative mRNA levels of Cyp17A1 in the liver, testis, iWATs, adrenal gland, brain, and pituitary gland of lean and db/db mice. n = 8 per group. (D) Western blots of total liver lysates from lean and db/db mice. (E) Relative mRNA levels of Cyp17A1 in the liver, testis, iWATs, adrenal gland, brain, and pituitary gland of lean and ob/ob mice. n = 8 per group. (F) Western blots of total liver lysates from lean and ob/ob mice. (G) Relative mRNA levels of Cyp17A1 in the livers of obese and normal weight humans. n = 16 per group. (H and I) Association between relative Cyp17A1 mRNA levels and fasting plasma glucose levels (H) and HbA1c (I) in humans (n = 32). ***P < 0.001, 2-tailed unpaired Student’s t test (A, C, E, and G) or Pearson’s correlation analysis (H and I). Data are represented as mean ± SD.