Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 20, Pages 7367-7372Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1406511111
Keywords
Akt/PKB; N-ethyl-N-nitrosourea
Categories
Funding
- National Institutes of Health [U19 AI100627]
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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.
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