Growth hormone acts on liver to stimulate autophagy, support glucose production, and preserve blood glucose in chronically starved mice
Growth hormone acts on liver to stimulate autophagy, support glucose production, and preserve blood glucose in chronically starved mice
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DOI：
10.1073/pnas.1901867116
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发表时间：
2019-04-09
影响因子：
11.1
通讯作者：
Liang, Guosheng
中科院分区：
文献类型：
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作者：
Fang, Fei;Shi, Xuanming;Liang, Guosheng
当老鼠连续几天受到60%卡路里的限制时，它们几乎失去了所有的身体脂肪。尽管这些动物缺乏能量储存，但它们的肝脏产生足够的葡萄糖，即使在禁食23小时后也能将血糖维持在可行的水平。这种适应是由血浆生长激素（GH）的显著增加介导的，这是由血浆生长激素释放肽（GH促分泌素）的增加引起的。在缺乏生长素释放肽的情况下，热量限制的小鼠由于葡萄糖产生减少而发生低血糖。为了确定GH作用的位点，在当前的研究中，我们使用CRISPR/Cas9和Cre重组酶技术来产生选择性地在肝脏（L-Ghr（-/-）小鼠）或脂肪组织（Fat-Ghr（-/-）小鼠）中缺乏GH受体的小鼠。当进行热量限制，然后禁食23小时，L-Ghr（-/-）小鼠，但不是Fat-Ghr（-/-）小鼠，发展低血糖症。L-Ghr（-/-）小鼠的血糖下降与肝脏甘油三酯的显著下降相关。通过注射乳酸盐或辛酸盐（支持糖异生的两种能量来源）可以预防低血糖。电子显微镜显示，在热量限制的对照小鼠的肝脏中存在广泛的自噬，但在L-Ghr（-/-）小鼠中没有。我们的结论是，生长激素通过其受体在肝脏中激活自噬，保存甘油三酯，增强造血，并防止低血糖症的热量限制的小鼠，一个模型的饥饿。
When mice are subjected to 60% calorie restriction for several days, they lose nearly all of their body fat. Although the animals lack energy stores, their livers produce enough glucose to maintain blood glucose at viable levels even after a 23-hour fast. This adaptation is mediated by a marked increase in plasma growth hormone (GH), which is elicited by an increase in plasma ghrelin, a GH secretagogue. In the absence of ghrelin, calorie-restricted mice develop hypoglycemia, owing to diminished glucose production. To determine the site of GH action, in the current study we used CRISPR/Cas9 and Cre recombinase technology to produce mice that lack GH receptors selectively in liver (L-Ghr(-/- )mice) or in adipose tissue (Fat-Ghr(-/- )mice). When subjected to calorie restriction and then fasted for 23 hours, the L-Ghr(-/-) mice, but not the Fat-Ghr(-/-) mice, developed hypoglycemia. The fall in blood glucose in L-Ghr(-/- )mice was correlated with a profound drop in hepatic triglycerides. Hypoglycemia was prevented by injection of lactate or octanoate, two sources of energy to support gluconeogenesis. Electron microscopy revealed extensive autophagy in livers of calorie-restricted control mice but not in L-Ghr(-/-) mice. We conclude that GH acts through its receptor in the liver to activate autophagy, preserve triglycerides, enhance gluconeogenesis, and prevent hypoglycemia in calorie-restricted mice, a model of famine.