Increased insulin sensitivity in paternal Gnas knockout mice is associated with increased lipid clearance
Increased insulin sensitivity in paternal Gnas knockout mice is associated with increased lipid clearance
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DOI：
10.1210/en.2004-0038
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发表时间：
2004-09-01
期刊：
影响因子：
4.8
通讯作者：
Weinstein, LS
中科院分区：
文献类型：
--
作者：
Chen, M;Haluzik, M;Weinstein, LS
G蛋白α亚基G(s) α是激素刺激的cAMP生成所必需的。G(s) α基因Gnas是一个具有多个印迹基因产物的复杂基因。杂合破坏Gnas父本等位基因（+/p-）的小鼠部分缺乏G(s) α，完全缺乏xlalpha，这是一种神经内分泌特异性G(s) α亚型。这种基因只由父系的Gnas等位基因表达。我们之前的研究表明，这些小鼠是高代谢和瘦的，并且胰岛素敏感性增加。我们现在进行了高胰岛素-正糖钳夹研究，证实了+/p-小鼠全身胰岛素敏感性显着增加。+/p-小鼠的肌肉、白色和棕色脂肪组织中胰岛素刺激的葡萄糖摄取分别增加了1.4倍、7倍和3.8倍，并显著抑制了肝脏的内源性葡萄糖产生。这与肝脏和肌肉对胰岛素的反应中胰岛素受体和下游效应物（Akt激酶）磷酸化增加有关。灌胃给药后，甘油三酯在+/p-小鼠中清除得更快。这与肝脏和肌肉甘油三酯含量降低以及肌肉酰基辅酶a氧化酶mRNA表达增加有关。抵抗素和脂联素在+/p-小鼠白色脂肪组织中过表达，但血清脂联素水平无差异。在+/p-小鼠中观察到的瘦表型和胰岛素敏感性增加可能是肌肉和其他组织中脂质氧化增加的结果。进一步的研究将阐明XLalphas缺乏是否导致了这些影响，如果是的话，XLalphas缺乏导致这种代谢表型的机制。
The G protein alpha-subunit G(s)alpha is required for hormone-stimulated cAMP generation. The G(s)alpha gene Gnas is a complex gene with multiple imprinted gene products. Mice with heterozygous disruption of the Gnas paternal allele (+/p-) are partially G(s)alpha deficient and totally deficient in XLalphas, a neuroendocrine-specific G(s)alpha isoform. that is expressed only from the paternal Gnas allele. We previously showed that these mice are hypermetabolic and lean and have increased insulin sensitivity. We now performed hyperinsulinemic-euglycemic clamp studies, which confirmed the markedly increased whole body insulin sensitivity in +/p- mice. +/p- mice had 1.4-, 7- and 3.8-fold increases in insulin-stimulated glucose uptake in muscle and white and brown adipose tissue, respectively, and markedly suppressed endogenous glucose production from the liver. This was associated with increased phosphorylation of insulin receptor and a downstream effector (Akt kinase) in both liver and muscle in response to insulin. Triglycerides cleared more rapidly in +/p- mice after a bolus administered by gavage. This was associated with decreased liver and muscle triglyceride content and increased muscle acyl-CoA oxidase mRNA expression. Resistin and adiponectin were overexpressed in white adipose tissue of +/p- mice, although there was no difference in serum adiponectin levels. The lean phenotype and increased insulin sensitivity observed in +/p- mice is likely a consequence of increased lipid oxidation in muscle and possibly other tissues. Further studies will clarify whether XLalphas deficiency is responsible for these effects and if so, the mechanism by which XLalphas deficiency leads to this metabolic phenotype.