Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell. 2018 Jan 11;172(1-2):234-248.e17. doi: 10.1016/j.cell.2017.12.001. Epub 2018 Jan 4.
The transition from the fed to the fasted state necessitates a shift from carbohydrate to fat metabolism that is thought to be mostly orchestrated by reductions in plasma insulin concentrations. Here, we show in awake rats that insulinopenia per se does not cause this transition but that both hypoleptinemia and insulinopenia are necessary. Furthermore, we show that hypoleptinemia mediates a glucose-fatty acid cycle through activation of the hypothalamic-pituitary-adrenal axis, resulting in increased white adipose tissue (WAT) lipolysis rates and increased hepatic acetyl-coenzyme A (CoA) content, which are essential to maintain gluconeogenesis during starvation. We also show that in prolonged starvation, substrate limitation due to reduced rates of glucose-alanine cycling lowers rates of hepatic mitochondrial anaplerosis, oxidation, and gluconeogenesis. Taken together, these data identify a leptin-mediated glucose-fatty acid cycle that integrates responses of the muscle, WAT, and liver to promote a shift from carbohydrate to fat oxidation and maintain glucose homeostasis during starvation.
从进食状态向禁食状态的转变需要从碳水化合物代谢向脂肪代谢转变，人们认为这种转变主要是通过降低血浆胰岛素浓度来协调的。在这里，我们在清醒的大鼠中表明，胰岛素缺乏本身并不会导致这种转变，而是瘦素缺乏和胰岛素缺乏都是必要的。此外，我们还表明，瘦素缺乏通过激活下丘脑-垂体-肾上腺轴介导葡萄糖-脂肪酸循环，导致白色脂肪组织（WAT）脂肪分解率增加和肝乙酰辅酶 A（CoA）含量增加，这对于维持饥饿期间的糖异生是必不可少的。我们还表明，在长时间饥饿中，由于葡萄糖-丙氨酸循环率降低导致的底物限制降低了肝线粒体补充、氧化和糖异生的速率。总之，这些数据确定了一种瘦素介导的葡萄糖-脂肪酸循环，它整合了肌肉、WAT 和肝脏的反应，以促进从碳水化合物向脂肪氧化的转变，并在饥饿期间维持葡萄糖稳态。
