Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1213, Lyon, France.
Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1033, Lyon, France.
Endocrinology. 2021 Jul 1;162(7). doi: 10.1210/endocr/bqab098.
Tamoxifen is a selective estrogen receptor modulator used to activate the CREERT2 recombinase, allowing tissue-specific and temporal control of the somatic mutagenesis to generate transgenic mice. Studies integrating development and metabolism require a genetic modification induced by a neonatal tamoxifen administration. Here, we investigate the effects of a neonatal tamoxifen administration on energy homeostasis in adult male and female C57BL/6J mice. C57BL/6J male and female mouse pups received a single injection of tamoxifen 1 day after birth (NTT) and were fed a high-fat/high-sucrose diet at 6 weeks of age. We measured weight, body composition, glucose and insulin tolerance, basal metabolism, and tibia length and weight in adult mice. The neonatal tamoxifen administration exerted long-term, sex-dependent effects on energy homeostasis. NTT female mice became overweight and developed impaired glucose control in comparison to vehicle-treated littermates. NTT females exhibited 60% increased fat mass, increased food intake, decreased physical activity and energy expenditure, impaired glucose and insulin tolerance, and fasting hyperglycemia and hyperinsulinemia. In contrast, NTT male mice exhibited a modest amelioration of glucose and insulin tolerance and long-term decreased lean mass linked to decreased bone weight. These results suggest that the neonatal tamoxifen administration exerted a marked and sex-dependent influence on adult energy homeostasis and bone weight and must therefore be used with caution for the development of transgenic mouse models regarding studies on energy homeostasis and bone biology.
他莫昔芬是一种选择性雌激素受体调节剂，用于激活 CREERT2 重组酶，允许组织特异性和时间控制体细胞突变，从而产生转基因小鼠。整合发育和代谢研究需要通过新生期他莫昔芬给药进行遗传修饰。在这里，我们研究了新生期他莫昔芬给药对雄性和雌性 C57BL/6J 成年小鼠能量平衡的影响。C57BL/6J 雄性和雌性幼鼠在出生后第 1 天接受单次他莫昔芬注射（NTT），并在 6 周龄时接受高脂肪/高蔗糖饮食喂养。我们在成年小鼠中测量体重、身体成分、葡萄糖和胰岛素耐量、基础代谢率以及胫骨长度和重量。新生期他莫昔芬给药对能量平衡产生了长期的、性别依赖性的影响。与接受载体处理的同窝幼鼠相比，NTT 雌性小鼠体重增加，并出现葡萄糖控制受损。NTT 雌性小鼠的脂肪量增加了 60%，食物摄入量增加，体力活动和能量消耗减少，葡萄糖和胰岛素耐量受损，出现空腹高血糖和高胰岛素血症。相比之下，NTT 雄性小鼠的葡萄糖和胰岛素耐量略有改善，并且长期的瘦体重减少与骨重量减少有关。这些结果表明，新生期他莫昔芬给药对成年能量平衡和骨重量产生了显著的、性别依赖性的影响，因此在开发涉及能量平衡和骨生物学研究的转基因小鼠模型时必须谨慎使用。
