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Author Notes:

To whom correspondence should be addressed: Fred G. Brazda Professor of Biochemistry, Louisiana School of Medicine, CSRB 406, New Orleans, LA 70112., Tel.: 504-568-4734; E-mail: salaha@lsuhsc.edu

S. K. A. and S. D. designed the study.

S. D., S. B., A. G., S. S. G., S. E., and T. I. performed the experiments.

D. M. helped with statistical analysis and S. K. A. and S. D. interpreted the data.

S. K. A. and S. D. wrote the manuscript.

F. M. J. helped with metabolism approaches.

We thank Dr. Kartik Shankar of University of Arkansas, Little Rock, AR for good discussions on indirect calorimetry and Dr. Dorota Wyczechowska of Louisiana State University Health Science Center (LSUHSC) for help with Seahorse experiments.

The authors declare that they have no conflicts of interest with the contents of this article.

Subjects:

Research Funding:

This work was supported in part by the Louisiana State University School of Medicine and the Fred G. Brazda Foundation.

Keywords:

  • AMP-activated kinase
  • AMPK
  • calorimetry
  • cell metabolism
  • cell migration
  • glucose
  • obesity

Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase

Tools:

Journal Title:

Journal of Biological Chemistry

Volume:

Volume 292, Number 41

Publisher:

, Pages 16833-16846

Type of Work:

Article | Final Publisher PDF

Abstract:

Nischarin (Nisch) is a key protein functioning as a molecular scaffold and thereby hosting interactions with several protein partners. To explore the physiological importance of Nisch, here we generated Nisch loss-of-function mutant mice and analyzed their metabolic phenotype. Nisch-mutant embryos exhibited delayed development, characterized by small size and attenuated weight gain. We uncovered the reason for this phenotype by showing that Nisch binds to and inhibits the activity of AMP-activated protein kinase (AMPK), which regulates energy homeostasis by suppressing anabolic and activating catabolic processes. The Nisch mutations enhanced AMPK activation and inhibited mechanistic target of rapamycin signaling in mouse embryonic fibroblasts as well as in muscle and liver tissues of mutant mice. Nisch-mutant mice also exhibited increased rates of glucose oxidation with increased energy expenditure, despite reduced overall food intake. Moreover, the Nisch-mutant mice had reduced expression of liver markers of gluconeogenesis associated with increased glucose tolerance. As a result, these mice displayed decreased growth and body weight. Taken together, our results indicate that Nisch is an important AMPK inhibitor and a critical regulator of energy homeostasis, including lipid and glucose metabolism.

Copyright information:

© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

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