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PRMT1 promotes hyperglycemia in a FoxO1-dependent manner, affecting glucose metabolism, during hypobaric hypoxia exposure, in rat model

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Abstract

Purpose

High-altitude (HA) environment causes changes in cellular metabolism among unacclimatized humans. Previous studies have revealed that insulin-dependent activation of protein kinase B (Akt) regulates metabolic processes via discrete transcriptional effectors. Moreover, protein arginine methyltransferase (PRMT)1-dependent arginine modification of forkhead box other (FoxO)1 protein interferes with Akt-dependent phosphorylation. The present study was undertaken to test the involvement of PRMT1 on FoxO1 activation during hypobaric hypoxia (HH) exposure in rat model.

Methods

Samples were obtained from normoxia control (NC) and HH-exposed (H) rats, subdivided according to the duration of HH exposure. To explore the specific role played by PRMT1 during HH exposure, samples from 1d pair-fed (PF) NC, 1d acute hypoxia-exposed (AH) placebo-treated, and 1d AH TC-E-5003-treated rats were investigated. Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) was performed to determine expressions of glycolytic, gluconeogenic enzymes, and insulin response regulating genes. Immuno-blot and enzyme linked immunosorbent assay (ELISA) were used for insulin response regulating proteins. Nuclear translocation of FoxO1 was analyzed using deoxyribonucleic acid (DNA)-binding ELISA kit.

Results

We observed HH-induced increase in glycolytic enzyme expressions in hepatic tissue unlike hypothalamic tissue. PRMT1 expression increased during HH exposure, causing insulin resistance and resulting increase in FoxO1 nuclear translocation, leading to hyperglycemia. Conversely, PRMT1 inhibitor treatment promoted inhibition of FoxO1 activity and increase in glucose uptake during HH exposure leading to reduction in blood-glucose and hepatic glycogen levels.

Conclusions

PRMT1 might have a potential importance as a therapeutic target for the treatment of HH-induced maladies.

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Acknowledgements

We thank Dr. N.K. Sethy and Dr. K. Ray for excellent technical support.

Author contributions

A.J.D., P.G., S.B., S.S. were involved in acquisition of data. S.B. conceived and designed the study, analyzed and interpretated the data, and drafted the article also. All authors contributed to the revising of the manuscript, and approved the final version of the manuscript.

Funding

The work was funded by the Defence Research and Development Organization (DRDO), Government of India. S.B., D.A.J., and P.G. are thankful to DRDO, and S.S. is thankful to the University Grants Commission (UGC) for junior/senior research fellowships.

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Authors and Affiliations

  1. Endocrinology & Metabolism Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054, India

    Susovon Bayen, Supriya Saini, Priya Gaur, Arul Joseph Duraisamy, Alpesh Kumar Sharma, Karan Pal & Praveen Vats

  2. Department of Applied Physiology, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054, India

    Shashi Bala Singh

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  1. Susovon Bayen
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Correspondence to Praveen Vats.

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The study protocol was approved by the Institutional Animal Ethics Committee.

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Bayen, S., Saini, S., Gaur, P. et al. PRMT1 promotes hyperglycemia in a FoxO1-dependent manner, affecting glucose metabolism, during hypobaric hypoxia exposure, in rat model. Endocrine 59, 151–163 (2018). https://doi.org/10.1007/s12020-017-1463-6

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