TY - JOUR
T1 - Mutation of mouse Samd4 causes leanness, myopathy, uncoupled mitochondrial respiration, and dysregulated mTORC1 signaling
AU - Chen, Zhe
AU - Holland, William
AU - Shelton, John M.
AU - Ali, Aktar
AU - Zhan, Xiaoming
AU - Won, Sungyong
AU - Tomisato, Wataru
AU - Liu, Chen
AU - Li, Xiaohong
AU - Moresco, Eva Marie Y
AU - Beutler, Bruce
PY - 2014/5/20
Y1 - 2014/5/20
N2 - 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.
AB - 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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U2 - 10.1073/pnas.1406511111
DO - 10.1073/pnas.1406511111
M3 - Article
C2 - 24799716
AN - SCOPUS:84901008920
SN - 0027-8424
VL - 111
SP - 7367
EP - 7372
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -