Profound Hypoglycemia in Starved, Ghrelin-deficient Mice Is Caused by Decreased Gluconeogenesis and Reversed by Lactate or Fatty Acids
Profound Hypoglycemia in Starved, Ghrelin-deficient Mice Is Caused by Decreased Gluconeogenesis and Reversed by Lactate or Fatty Acids
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DOI：
10.1074/jbc.m112.358051
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发表时间：
2012-05-25
影响因子：
4.8
通讯作者：
Zhao, Tong-Jin
中科院分区：
文献类型：
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作者：
Li, Robert Lin;Sherbet, Daniel P.;Zhao, Tong-Jin
当小鼠受到 7 天的热量限制（正常食物摄入量的 40%）时，体内脂肪会消失，但只要动物产生生长素释放肽（一种刺激生长激素分泌的辛酰化肽），血糖就会保持不变。通过敲除编码生长素释放肽O-酰基转移酶（连接所需辛酸）的基因或生长素释放肽本身，可以使小鼠缺乏生长素释放肽。热量限制、脂肪耗尽的生长素释放肽 O-酰基转移酶或生长素释放肽敲除小鼠无法表现出生长激素的正常增加，并且在禁食 18-23 小时时出现严重低血糖。与经过类似处理的 WT 小鼠相比，山羊 (-/-) 小鼠的葡萄糖产量减少了 60%。血浆乳酸和丙酮酸也较低。注射乳酸、丙酮酸、丙氨酸或脂肪酸可以恢复山羊(-/-)小鼠的血糖。因此，当通过热量限制减少身体脂肪时，生长素释放肽会刺激生长激素分泌，从而即使在消除食物摄入的情况下也能维持葡萄糖的产生。在患有神经性厌食症或恶性营养不良症的人类中，生长激素释放肽和生长激素会升高，就像在脂肪耗尽的小鼠中一样。我们认为这两种激素可以像老鼠一样延长饥饿人类的生存时间。
When mice are subjected to 7-day calorie restriction (40% of normal food intake), body fat disappears, but blood glucose is maintained as long as the animals produce ghrelin, an octanoylated peptide that stimulates growth hormone secretion. Mice can be rendered ghrelin-deficient by knock-out of the gene encoding either ghrelin O-acyltransferase, which attaches the required octanoate, or ghrelin itself. Calorie-restricted, fat-depleted ghrelin O-acyltransferase or ghrelin knock-out mice fail to show the normal increase in growth hormone and become profoundly hypoglycemic when fasted for 18-23 h. Glucose production in Goat(-/-) mice was reduced by 60% when compared with similarly treated WT mice. Plasma lactate and pyruvate were also low. Injection of lactate, pyruvate, alanine, or a fatty acid restored blood glucose in Goat(-/-) mice. Thus, when body fat is reduced by calorie restriction, ghrelin stimulates growth hormone secretion, which allows maintenance of glucose production, even when food intake is eliminated. In humans with anorexia nervosa or kwashiorkor, ghrelin and growth hormone are known to be elevated, just as they are in fat-depleted mice. We suggest that these two hormones prolong survival in starved humans as they do in mice.