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Dehydroepiandrosterone protects against hepatic glycolipid metabolic disorder and insulin resistance induced by high fat via activation of AMPK-PGC-1α-NRF-1 and IRS1-AKT-GLUT2 signaling pathways

International Journal of Obesity volume 44, pages 1075–1086 (2020)Cite this article

Subjects

Abstract

Background/objectives

Mitochondrial dysfunction, oxidative stress, or fatty liver are the key pathophysiological features for insulin resistance and obesity. Dehydroepiandrosterone (DHEA) can ameliorate obesity and insulin resistance; however, the mechanisms of these actions are poorly understood. The present study aimed to investigate the effect and possible mechanism of DHEA against glycolipid metabolic disorder and insulin resistance.

Subjects/methods

Rats fed a high-fat diet (HFD) and palmitic acid (PA)-induced BRL-3A cells were employed to analyze the effect of DHEA on factors related to metabolic disorder and insulin resistance in vivo and in vitro.

Results

DHEA prevented lipid metabolism disorders by enhancing phospho (p)-protein kinase AMP-activated catalytic subunit alpha (AMPKα) (Thr172) protein level and its downstream lipid metabolism-related factors in liver of rats fed an HFD or in PA-induced BRL-3A cells. Meanwhile, DHEA ameliorated mitochondrial dysfunction through activation of the AMPK-peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)-nuclear respiratory factor-1 (NRF-1) pathway, which represented as the enhancing of the mtDNA copy number, ATP level, and membrane potential, and decreasing of reactive oxygen species production. Moreover, DHEA alleviated insulin resistance via increasing the phosphorylated insulin receptor substrate 1 (p-IRS1) (Tyr612) level and decreasing that of p-IRS1 (Ser307) level in liver of rats fed an HFD or in PA-induced BRL-3A cells, which subsequently enhanced p-protein kinase B (AKT) (Ser473) and membrane glucose transporter type 2 (GLUT2) expression levels.

Conclusions

The protective effect of DHEA on high-fat-induced hepatic glycolipid metabolic disorder and insulin resistance are achieved through activation of the AMPK-PGC-1α-NRF-1 and IRS1-AKT-GLUT2 signaling pathways. The results provide compelling evidence for the mechanism by which DHEA prevents glycolipid metabolic disorder, and suggest its potential applications for controlling diabetes and obesity in animals and humans.

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Fig. 1: Effect of DHEA on lipid accumulation, glucose uptake, and ATP levels in BRL-3A cells under metabolic disorders condition.
Fig. 2: Protective effect of DHEA on insulin resistance in PA-induced BRL-3A cells.
Fig. 3: DHEA ameliorates energy metabolism dysfunction in PA-induced BRL-3A cells.
Fig. 4: Impact of DHEA on AMPK and insulin signaling pathways in PA-induced BRL-3A cells.
Fig. 5: Role of NRF-1 in DHEA-mediated attenuation of PA-elicited oxidative stress and mitochondrial dysfunction in BRL-3A cells.
Fig. 6: Proposed model by which DHEA prevents glycolipid metabolic disorder and insulin resistance.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant number 31572483); the Fundamental Research Funds for the Central Universities (grant number KYDZ201901); the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); and the Postgraduate Research and Practice Innovation Program of Jiangsu Province (KYCX18_0715).

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Authors and Affiliations

  1. Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China

    Longlong Li, Yao Yao, Jinlong Zhao, Ji Cao & Haitian Ma

  2. MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China

    Longlong Li, Yao Yao, Jinlong Zhao, Ji Cao & Haitian Ma

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Li, L., Yao, Y., Zhao, J. et al. Dehydroepiandrosterone protects against hepatic glycolipid metabolic disorder and insulin resistance induced by high fat via activation of AMPK-PGC-1α-NRF-1 and IRS1-AKT-GLUT2 signaling pathways. Int J Obes 44, 1075–1086 (2020). https://doi.org/10.1038/s41366-019-0508-8

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