High fat feeding unmasks variable insulin responses in male C57BL/6 mouse substrains.
High fat feeding unmasks variable insulin responses in male C57BL/6 mouse substrains.
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DOI：
10.1530/joe-16-0377
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Zraika S
中科院分区：
文献类型：
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作者：
Hull RL;Willard JR;Struck MD;Barrow BM;Brar GS;Andrikopoulos S;Zraika S
小鼠模型被广泛用于阐明2型糖尿病的潜在机制。遗传背景深刻影响代谢表型;因此选择适当的模型至关重要。虽然小鼠品系之间的代谢反应的变异性现在已被充分认识，但它也发生在C57 BL/6小鼠中，其中存在几个亚品系。这种株内变异性知之甚少，可能源于遗传和/或环境差异。为了更好地定义菌株内变异性，我们对来自C57 BL/6亚株6 J、6 JWehi、6 NJ、6 NHsd、6 NTac和6 NCrl的胰岛素分泌进行了第一次全面比较。在体外，葡萄糖刺激的胰岛素分泌与Nnt突变状态相关，其中来自C57 BL/6 J小鼠的胰岛中的反应一致低于C57 BL/6 N小鼠。相比之下，在体内胰岛素反应18周的低脂肪喂养显示没有任何六个亚株之间的差异。当用高脂饮食攻击18周时，C57 BL/6 J亚株的胰岛素释放也有类似的增加。然而，C57 BL/6 N亚株之间的变异性很明显。令人惊讶的是，6 NJ小鼠在高脂肪喂养后没有显示出胰岛素释放的增加，导致随后的高血糖症。高脂喂养的C57 BL/6 N小鼠中胰岛素反应的变异性不能用胰岛素敏感性、体重、食物摄入或β细胞面积的差异来解释。相反，尚未确定的遗传和/或环境因素可能是贡献者。总之，我们的研究结果强调，在将体外研究的数据外推到体内情况时应谨慎，并为代谢研究选择适当的C57 BL/6亚株提供信息。
Mouse models are widely used for elucidating mechanisms underlying type 2 diabetes. Genetic background profoundly affects metabolic phenotype; therefore selecting the appropriate model is critical. While variability in metabolic responses between mouse strains is now well-recognized, it also occurs within C57BL/6 mice, of which several substrains exist. This within-strain variability is poorly understood, and could emanate from genetic and/or environmental differences. To better define the within-strain variability, we performed the first comprehensive comparison of insulin secretion from C57BL/6 substrains 6J, 6JWehi, 6NJ, 6NHsd, 6NTac and 6NCrl. In vitro, glucose-stimulated insulin secretion correlated with Nnt mutation status, wherein responses were uniformly lower in islets from C57BL/6J versus C57BL/6N mice. In contrast, in vivo insulin responses following 18 weeks of low fat feeding showed no differences among any of the six substrains. When challenged with a high fat diet for 18 weeks, C57BL/6J substrains responded with a similar increase in insulin release. However, variability was evident among C57BL/6N substrains. Strikingly, 6NJ mice showed no increase in insulin release after high fat feeding, contributing to the ensuing hyperglycemia. The variability in insulin responses among high fat-fed C57BL/6N mice could not be explained by differences in insulin sensitivity, body weight, food intake or beta-cell area. Rather, as yet unidentified genetic and/or environmental factor(s) are likely contributors. Together, our findings emphasize that caution should be exercised in extrapolating data from in vitro studies to the in vivo situation, and inform on selecting the appropriate C57BL/6 substrain for metabolic studies.