Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid E28029, Spain.
Cell Metab. 2012 Mar 7;15(3):382-94. doi: 10.1016/j.cmet.2012.02.001.
Aging in worms and flies is regulated by the PI3K/Akt/Foxo pathway. Here we extend this paradigm to mammals. Pten(tg) mice carrying additional genomic copies of Pten are protected from cancer and present a significant extension of life span that is independent of their lower cancer incidence. Interestingly, Pten(tg) mice have an increased energy expenditure and protection from metabolic pathologies. The brown adipose tissue (BAT) of Pten(tg) mice is hyperactive and presents high levels of the uncoupling protein Ucp1, which we show is a target of Foxo1. Importantly, a synthetic PI3K inhibitor also increases energy expenditure and hyperactivates the BAT in mice. These effects can be recapitulated in isolated brown adipocytes and, moreover, implants of Pten(tg) fibroblasts programmed with Prdm16 and Cebpβ form subcutaneous brown adipose pads more efficiently than wild-type fibroblasts. These observations uncover a role of Pten in promoting energy expenditure, thus decreasing nutrient storage and its associated damage.
在蠕虫和苍蝇中，衰老受 PI3K/Akt/Foxo 途径调控。在这里，我们将这一范例扩展到哺乳动物。携带额外基因组拷贝的 Pten(tg) 小鼠可预防癌症，并显著延长寿命，而与癌症发病率降低无关。有趣的是，Pten(tg) 小鼠的能量消耗增加，并能预防代谢性疾病。Pten(tg) 小鼠的棕色脂肪组织 (BAT) 过度活跃，高水平表达解偶联蛋白 Ucp1，我们发现它是 Foxo1 的靶点。重要的是，一种合成的 PI3K 抑制剂也能增加能量消耗并使 BAT 过度活跃。这些作用可以在分离的棕色脂肪细胞中重现，此外，用 Prdm16 和 Cebpβ 编程的 Pten(tg) 成纤维细胞的植入物比野生型成纤维细胞更有效地形成皮下棕色脂肪垫。这些观察结果揭示了 Pten 在促进能量消耗中的作用，从而减少营养物质的储存及其相关损伤。
