Division of Life Sciences, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul, 02841, Korea.
Nat Commun. 2017 Nov 30;8(1):1878. doi: 10.1038/s41467-017-01878-6.
Liver plays a crucial role in controlling energy homeostasis in mammals, although the exact mechanism by which it influences other peripheral tissues has yet to be addressed. Here we show that Creb regulates transcriptional co-activator (Crtc) 2 is a major regulator of whole-body energy metabolism. Crtc2 liver-specific knockout lowers blood glucose levels with improved glucose and insulin tolerance. Liver-specific knockout mice display increased energy expenditure with smaller lipid droplets in adipose depots. Both plasma and hepatic Fgf21 levels are increased in Crtc2 liver-specific knockout mice, as a result of the reduced miR-34a expression regulated by Creb/Crtc2 and the induction of Sirt1 and Pparα. Ectopic expression of miR-34a reverses the metabolic changes in knockout liver. We suggest that Creb/Crtc2 negatively regulates the Sirt1/Pparα/Fgf21 axis via the induction of miR-34a under diet-induced obesity and insulin-resistant conditions.
肝脏在哺乳动物的能量平衡控制中起着至关重要的作用，尽管它影响其他外周组织的确切机制尚未得到解决。在这里，我们表明，Creb 调节转录共激活因子（Crtc）2 是全身能量代谢的主要调节剂。Crtc2 肝脏特异性敲除可降低血糖水平，并改善葡萄糖和胰岛素耐受性。肝脏特异性敲除小鼠表现出更高的能量消耗，脂肪组织中的脂肪滴更小。由于 Creb/Crtc2 调节的 miR-34a 表达减少和 Sirt1 和 Pparα 的诱导，血浆和肝 Fgf21 水平在 Crtc2 肝脏特异性敲除小鼠中增加。miR-34a 的异位表达逆转了敲除肝脏的代谢变化。我们认为，在饮食诱导的肥胖和胰岛素抵抗条件下，Creb/Crtc2 通过诱导 miR-34a 负调节 Sirt1/Pparα/Fgf21 轴。
