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中国福利彩票注册:Growth hormone acts on liver to stimulate autophagy, support glucose production, and preserve blood glucose in chronically starved mice
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Nine million people starve to death annually. To understand starvation, we created a mouse model in which the mice receive a daily meal that contains 40% of normal calories. They consume each meal within 1 hour and fast for 23 hours. Normal mice maintain viable levels of blood glucose by increasing hepatic glucose production. Gluconeogenesis requires elevated plasma growth hormone (GH) and is accompanied by hepatic autophagy. GH-deficient mice become hypoglycemic, owing to decreased autophagy and glucose production. Here we show that mice lacking the liver GH receptor have reduced autophagy and become hypoglycemic. These data demonstrate that GH acts through its receptor in the liver to induce autophagy and enhance glucose production, maintaining blood glucose during famine.
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.
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Author contributions: F.F., X.S., M.S.B., J.L.G., and G.L. designed research; F.F., X.S., and G.L. performed research; F.F., X.S., M.S.B., J.L.G., and G.L. analyzed data; and F.F., M.S.B., J.L.G., and G.L. wrote the paper.
Reviewers: R.G.S., The Scripps Research Institute; and M.O.T., University of Virginia Health Sciences Center.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1901867116/-/DCSupplemental.
Published under the PNAS license.