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Proc Natl Acad Sci U S A. 2014 May 20;111(20):7367-72. doi: 10.1073/pnas.1406511111. Epub 2014 May 5.

Mutation of mouse Samd4 causes leanness, myopathy, uncoupled mitochondrial respiration, and dysregulated mTORC1 signaling.

Author information

1
Center for Genetics of Host Defense.
2
Department of Internal Medicine, Touchstone Diabetes Center.
3
Department of Internal Medicine, Division of Cardiology.
4
Department of Internal Medicine, and.
5
Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX 75390.
6
Center for Genetics of Host Defense, bruce.beutler@utsouthwestern.edu.

Abstract

Sterile alpha motif domain containing protein 4 (Samd4) is an RNA binding protein that mediates translational repression. We identified a Samd4 missense mutation, designated supermodel, that caused leanness and kyphosis associated with myopathy and adipocyte defects in C57BL/6J mice. The supermodel mutation protected homozygous mice from high fat diet-induced obesity, likely by promoting enhanced energy expenditure through uncoupled mitochondrial respiration. Glucose tolerance was impaired due to diminished insulin release in homozygous mutant mice. The defects of metabolism in supermodel mice may be explained by dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling, evidenced by hypophosphorylation of 4E-BP1 and S6 in muscle and adipose tissues of homozygous mice. Samd4 may interface with mTORC1 signaling through an interaction with 14-3-3 proteins and with Akt, which phosphorylates Samd4 in vitro.

KEYWORDS:

Akt/PKB; N-ethyl-N-nitrosourea

PMID:
24799716
PMCID:
PMC4034201
DOI:
10.1073/pnas.1406511111
[Indexed for MEDLINE]
Free PMC Article

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