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J Biol Chem. 2017 Oct 13;292(41):16833-16846. doi: 10.1074/jbc.M117.784256. Epub 2017 Aug 24.

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

Author information

1
From the Department of Biochemistry and Molecular Biology, School of Medicine, and.
2
the Center for Biochemistry and Microbial Sciences, Central University of Punjab, City Campus Mansa Rd., Bathinda-151001, India.
3
the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322.
4
the Pontificia Universidad Javeriana, 11001000 Bogotá, Colombia.
5
the Department of Cancer Biology, Kansas University Medical Center, Kansas City, Kansas 66160, and.
6
Department of Biostatistics, School of Public Health, Louisiana State University Health Science Center, New Orleans, Louisiana 70112.
7
the Division of Endocrinology, Tulane University School of Medicine, New Orleans, Louisiana 70112.
8
From the Department of Biochemistry and Molecular Biology, School of Medicine, and salaha@lsuhsc.edu.

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.

KEYWORDS:

AMP-activated kinase (AMPK); calorimetry; cell metabolism; cell migration; glucose; obesity

PMID:
28842496
PMCID:
PMC5641867
DOI:
10.1074/jbc.M117.784256
[Indexed for MEDLINE]
Free PMC Article

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