The Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) Regulates Adipose Tissue Accumulation and Adipocyte Insulin Sensitivity in Vivo
The Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) Regulates Adipose Tissue Accumulation and Adipocyte Insulin Sensitivity in Vivo
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DOI：
10.1074/jbc.m110.107680
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发表时间：
2010-06-11
影响因子：
4.8
通讯作者：
Cohen, Ronald N.
中科院分区：
文献类型：
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作者：
Sutanto, Maria M.;Ferguson, Kelly K.;Cohen, Ronald N.
类维生素A和甲状腺激素受体（SMRT）的沉默介体作为核受体和其他因子的辅阻遏物。最近的证据表明，SMRT是一个重要的调节代谢，但其在体内脂肪细胞功能的作用仍不清楚。我们建立了杂合SMRT基因敲除（SMRT+/-）小鼠，以研究SMRT在脂肪细胞中的功能以及对脂肪细胞胰岛素敏感性的调节。我们表明，SMRT+/-小鼠在常规饮食中体重正常，但在高脂肪饮食（HFD）中肥胖增加。这种表型的机制是复杂的，但似乎是由于更小的皮下脂肪细胞的数量增加以及瘦素表达减少，导致更大的热量摄入的组合。此外，来自这些小鼠的小鼠胚胎成纤维细胞（MEFs）的脂肪生成增加。然而，通过胰岛素诱导的Akt磷酸化和胰岛素介导的脂解抑制测量的脂肪细胞胰岛素敏感性在SMRT+/-脂肪细胞中增强。这些发现表明，SMRT调节瘦素的表达，并限制脂肪质量的能力，扩大增加热量摄入，但SMRT也负调节脂肪细胞胰岛素敏感性。
The silencing mediator of retinoid and thyroid hormone receptors (SMRT) serves as a corepressor for nuclear receptors and other factors. Recent evidence suggests that SMRT is an important regulator of metabolism, but its role in adipocyte function in vivo remains unclear. We generated heterozygous SMRT knock-out (SMRT+/-) mice to investigate the function of SMRT in the adipocyte and the regulation of adipocyte insulin sensitivity. We show that SMRT+/- mice are normal weight on a regular diet, but develop increased adiposity on a high-fat diet (HFD). The mechanisms underlying this phenotype are complex, but appear to be due to a combination of an increased number of smaller subcutaneous adipocytes as well as decreased leptin expression, resulting in greater caloric intake. In addition, adipogenesis of mouse embryonic fibroblasts (MEFs) derived from these mice was increased. However, adipocyte insulin sensitivity, measured by insulin-induced Akt phosphorylation and insulin-mediated suppression of lipolysis, was enhanced in SMRT+/- adipocytes. These finding suggest that SMRT regulates leptin expression and limits the ability of fat mass to expand with increased caloric intake, but that SMRT also negatively regulates adipocyte insulin sensitivity.