Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan, 236-0004, Japan.
Sci Rep. 2017 Jun 23;7(1):4119. doi: 10.1038/s41598-017-04304-5.
Growth factor signaling via insulin receptor (IR) and IGF-1 receptor (IGF1R) plays several important roles in the pathogenesis of metabolic syndrome and diabetes. OSI-906 (linsitinib), an anti-tumor drug, is an orally bioavailable dual inhibitor of IR and IGF1R. To investigate the recovery from metabolic changes induced by the acute inhibition of IR and IGF1R in adult mice, mice were treated with OSI-906 or a vehicle for 7 days and the results were analyzed on the last day of injection (Day 7) or after 7 or 21 days of withdrawal (Day 14 or Day 28). On day 7, the visceral white fat mass was significantly reduced in mice treated with OSI-906 accompanied by a reduced expression of leptin and an increased expression of the lipolysis-related genes Lpl and Atgl. Interestingly, the lipoatrophy and the observed changes in gene expression were completely reversed on day 14. Similarly, liver steatosis and β cell proliferation were transiently observed on day 7 but had disappeared by day 14. Taken together, these results suggest that this model for the acute inhibition of systemic IR/IGF1R signaling may be useful for investigating the recovery from metabolic disorders induced by impaired growth factor signaling.
胰岛素受体 (IR) 和 IGF-1 受体 (IGF1R) 的生长因子信号转导在代谢综合征和糖尿病的发病机制中发挥着重要作用。OSI-906（linisitinib）是一种抗肿瘤药物，是一种口服生物可利用的 IR 和 IGF1R 的双重抑制剂。为了研究急性抑制 IR 和 IGF1R 对成年小鼠代谢变化的恢复情况，用 OSI-906 或载体处理小鼠 7 天，并在最后一天注射（第 7 天）或停药 7 或 21 天后（第 14 天或第 28 天）分析结果。第 7 天，OSI-906 处理的小鼠内脏白色脂肪质量显著减少，伴随着瘦素表达降低和脂解相关基因 Lpl 和 Atgl 表达增加。有趣的是，第 14 天时，脂肪萎缩和观察到的基因表达变化完全逆转。同样，第 7 天观察到肝脂肪变性和β细胞增殖，但第 14 天时已消失。总之，这些结果表明，这种急性抑制全身 IR/IGF1R 信号的模型可能有助于研究因生长因子信号受损而引起的代谢紊乱的恢复。
