The Shc locus regulates insulin signaling and adiposity in mammals.
The Shc locus regulates insulin signaling and adiposity in mammals.
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DOI：
10.1111/j.1474-9726.2010.00641.x
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发表时间：
2011-02
期刊：
影响因子：
7.8
通讯作者：
Cortopassi GA
中科院分区：
文献类型：
--
作者：
Tomilov AA;Ramsey JJ;Hagopian K;Giorgio M;Kim KM;Lam A;Migliaccio E;Lloyd KC;Berniakovich I;Prolla TA;Pelicci P;Cortopassi GA
p66Shc基因敲除菌株（ShcP）的寿命先前被归因于增强的抗逆性和线粒体的改变。ShcP组织的微阵列显示胰岛素信号的改变。与此观察结果一致，ShcP小鼠在机体和组织水平上具有更高的胰岛素敏感性和葡萄糖耐受性，新型p66Shc敲除（ShcL）也是如此。细胞系中Shc表达的增加和减少分别降低和增加胰岛素敏感性，这与p66Shc作为胰岛素信号抑制因子的功能一致。然而，两种p66Shc敲除菌株之间也存在差异。ShcL小鼠更胖，对高脂肪饮食更敏感，它们的脂肪比对照组对胰岛素更敏感。另一方面，ShcP小鼠更瘦，对高脂肪饮食有抵抗力，它们的脂肪对胰岛素的敏感性低于对照组。ShcL和ShcP菌株在C57Bl/6背景下都是高度近交的，因此我们研究了Shc位点的基因表达，该基因编码p66、p52和p46三个亚型。两株中均不存在p66异构体；因此，将“瘦”表型归因于其余差异的是其他两种同种异构体的表达。ShcL小鼠具有p66Shc的精确缺失和p52和p46Shc亚型在所有组织中的正常表达；因此，p66Shc的简单缺失会导致“肥胖”表型。然而，除了p66Shc缺失外，ShcP小鼠在白色脂肪中的p46Shc表达增加了四倍。因此，脂肪中的p46Shc过表达，而不是p66Shc缺失，可能是导致ShcP小鼠脂肪中脂肪减少和胰岛素敏感性降低的原因，这对该品系的寿命有影响。
Longevity of a p66Shc knockout strain (ShcP) was previously attributed to increased stress resistance and altered mitochondria. Microarrays of ShcP tissues indicated alterations in insulin signaling. Consistent with this observation, ShcP mice were more insulin sensitive and glucose tolerant at organismal and tissue levels, as was a novel p66Shc knockout (ShcL). Increasing and decreasing Shc expression in cell lines decreased and increased insulin sensitivity, respectively – consistent with p66Shc's function as a repressor of insulin signaling. However, differences between the two p66Shc knockout strains were also observed. ShcL mice were fatter and susceptible to fatty diets, and their fat was more insulin sensitive than controls. On the other hand, ShcP mice were leaner and resisted fatty diets, and their adipose was less insulin sensitive than controls. ShcL and ShcP strains are both highly inbred on the C57Bl/6 background, so we investigated gene expression at the Shc locus, which encodes three isoforms, p66, p52, and p46. Isoform p66 is absent in both strains; thus, the remaining difference to which to attribute the ‘lean’ phenotype is expression of the other two isoforms. ShcL mice have a precise deletion of p66Shc and normal expression of p52 and p46Shc isoforms in all tissues; thus, a simple deletion of p66Shc results in a ‘fat’ phenotype. However, ShcP mice in addition to p66Shc deletion have a fourfold increase in p46Shc expression in white fat. Thus, p46Shc overexpression in fat, rather than p66Shc deletion, is the likely cause of decreased adiposity and reduced insulin sensitivity in the fat of ShcP mice, which has implications for the longevity of the strain.
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影响因子：
64.5
作者：
Giorgio, M;Migliaccio, E;Pelicci, PG
通讯作者：
Pelicci, PG
影响因子：
4.8
作者：
Coschigano, KT;Holland, AN;Kopchick, JJ
通讯作者：
Kopchick, JJ
DOI：
10.1093/gerona/63.5.447
发表时间：
2008-05-01
影响因子：
5.1
作者：
Atzmon, Gil;Pollin, Toni I.;Barzilai, Nir
通讯作者：
Barzilai, Nir
影响因子：
4.2
作者：
Barzilai, N;Gabriely, I
通讯作者：
Gabriely, I
影响因子：
2.9
作者：
Hunter, WS;Croson, WB;Meliska, CJ
通讯作者：
Meliska, CJ