Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress

Edited by Marc R. Montminy, Salk Institute for Biological Studies, La Jolla, CA, and approved January 6, 2011 (received for review May 18, 2010)
January 31, 2011
108 (7) 2939-2944

Abstract

Chronic endoplasmic reticulum (ER) stress was recently revealed to affect hypothalamic neuroendocrine pathways that regulate feeding and body weight. However, it remains unexplored whether brain ER stress could use a neural route to rapidly cause the peripheral disorders that underlie the development of type 2 diabetes (T2D) and the metabolic syndrome. Using a pharmacologic model that delivered ER stress inducer thapsigargin into the brain, this study demonstrated that a short-term brain ER stress over 3 d was sufficient to induce glucose intolerance, systemic and hepatic insulin resistance, and blood pressure (BP) increase. The collection of these changes was accompanied by elevated sympathetic tone and prevented by sympathetic suppression. Molecular studies revealed that acute induction of metabolic disorders via brain ER stress was abrogated by NF-κB inhibition in the hypothalamus. Therapeutic experiments further revealed that acute inhibition of brain ER stress with tauroursodeoxycholic acid (TUDCA) partially reversed obesity-associated metabolic and blood pressure disorders. In conclusion, ER stress in the brain represents a mediator of the sympathetic disorders that underlie the development of insulin resistance syndrome and T2D.

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Acknowledgments

This study was supported by National Institutes of Health Grants R01 DK078750 and R01 AG031774 and American Diabetes Association Junior Faculty Award 1-07-JF-09 (all to D.C.).

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Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 108 | No. 7
February 15, 2011
PubMed: 21282643

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Submission history

Published online: January 31, 2011
Published in issue: February 15, 2011

Acknowledgments

This study was supported by National Institutes of Health Grants R01 DK078750 and R01 AG031774 and American Diabetes Association Junior Faculty Award 1-07-JF-09 (all to D.C.).

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Sudarshana Purkayastha
Department of Molecular Pharmacology and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461; and
Hai Zhang
Department of Molecular Pharmacology and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461; and
Guo Zhang
Department of Molecular Pharmacology and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461; and
Zaghloul Ahmed
Department of Physical Therapy and Neuroscience Program, College of Staten Island/City University of New York, Staten Island, NY 10314
Yi Wang
Department of Molecular Pharmacology and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461; and
Dongsheng Cai1 [email protected]
Department of Molecular Pharmacology and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461; and

Notes

1
To whom correspondence should be addressed. E-mail: [email protected].
Author contributions: D.C. designed research; S.P., H.Z., G.Z., Z.A., and Y.W. performed research; S.P., H.Z., G.Z., Z.A., and D.C. analyzed data; and S.P. and D.C. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress
    Proceedings of the National Academy of Sciences
    • Vol. 108
    • No. 7
    • pp. 2631-3092

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