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 4

17-OHP promotes hyperglycemia and insulin resistance in vivo.

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17-OHP promotes hyperglycemia and insulin resistance in vivo. (A) Wester...
(A) Western blots showing the protein levels of Cyp17A1 in the livers of C57BL/6 mice transfected with adenovirus containing Cyp17A1 or GFP. (B and C) 17-OHP concentrations in the livers and plasma from mice overexpressing Cyp17A1 or GFP. (D–G) Blood glucose levels on postinjection day 5 (D), GTTs and ITTs on postinjection days 7 and 10, respectively (E and F), and plasma insulin levels (G) in 2 groups of mice. (H) Western blots showing the protein levels of phosphorylated AKT (serine 473) and total AKT in the livers of mice overexpressing Cyp17A1 or GFP. (I) PTTs in the 2 groups of mice on postinjection day 13. (J) Relative mRNA levels of PEPCK and G6Pase in the liver. (K) Liver TG contents. (L) Oil red O–stained liver sections. Original magnification, ×200. 2 × 109 PFUs per mouse were delivered into C57BL/6 mice through the tail vein. Sixteen days later, mice were sacrificed for analysis (A–C, G, H, and J–L). n = 6 per group. Data are represented as mean ± SD. *P < 0.05; **P < 0.01; and ***P < 0.001, 2-tailed unpaired Student’s t test (B–D, G, J, and K); 1-way ANOVA followed by Student-Newman-Keuls test (E, F, and I).