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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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 5

Ablation of hepatic GR attenuates 17-OHP–induced metabolic side effects.

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Ablation of hepatic GR attenuates 17-OHP–induced metabolic side effects....
(A) Western blot results showing GR protein levels in the livers of mice injected with adenoviral shRNA targeting GR or the NC. (B–D) Blood glucose levels on postinjection day 8 (B), plasma insulin levels (C), and hepatic TG content (D). (E) Oil red O staining of liver sections. Original magnification, ×200. (F–H) GTTs (F), ITTs (G), and PTTs (H) on postinjection days 10, 12, and 14, respectively. C57BL/6 mice were injected with GR shRNA or control shRNA at a dose of 4 × 109 PFUs per mouse through the tail vein. On postinjection day 2, mice were given 17-OHP or corn oil (vehicle) daily at doses of 50 mg/kg body weight by i.p. injection for another 14 days. Then mice were sacrificed for analysis (A, C–E). n = 7 per each subgroup. Data are represented as mean ± SD. **P < 0.01, and ***P < 0.001, 1-way ANOVA followed by the Student-Newman-Keuls test (B–D and F–H).