Growth hormone acts on liver to stimulate autophagy, support glucose production, and preserve blood glucose in chronically starved mice

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7449-7454
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number15
DOIs
StatePublished - Apr 9 2019

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Autophagy
Growth Hormone
Blood Glucose
Glucose
Liver
Hypoglycemia
Ghrelin
Gluconeogenesis
Adipose Tissue
Triglycerides
Clustered Regularly Interspaced Short Palindromic Repeats
Fats
Somatotropin Receptors
Starvation
Lactic Acid
Electron Microscopy
Technology
Injections

Keywords

  • Calorie restriction
  • Ghrelin
  • Hepatic growth hormone receptors
  • Hypoglycemia
  • Liver-specific knockout mice

ASJC Scopus subject areas

  • General

Cite this

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title = "Growth hormone acts on liver to stimulate autophagy, support glucose production, and preserve blood glucose in chronically starved mice",
abstract = "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.",
keywords = "Calorie restriction, Ghrelin, Hepatic growth hormone receptors, Hypoglycemia, Liver-specific knockout mice",
author = "Fei Fang and Xuanming Shi and Brown, {Michael S} and Goldstein, {Joseph L} and Guosheng Liang",
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T1 - Growth hormone acts on liver to stimulate autophagy, support glucose production, and preserve blood glucose in chronically starved mice

AU - Fang, Fei

AU - Shi, Xuanming

AU - Brown, Michael S

AU - Goldstein, Joseph L

AU - Liang, Guosheng

PY - 2019/4/9

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N2 - 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.

AB - 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.

KW - Calorie restriction

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