GCN2 drives diurnal patterns in the hepatic integrated stress response and maintains circadian rhythms in whole body metabolism during amino acid insufficiency.

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 Epub Date: 2024-08-28 DOI:10.1152/ajpendo.00129.2024
Jordan L Levy, Emily T Mirek, Esther M Rodriguez, Maria J Tolentino, Brian A Zalma, Troy A Roepke, Ronald C Wek, Ruifeng Cao, Tracy G Anthony
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Abstract

Disruptions in circadian rhythms are associated with an increased risk of developing metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor of amino acid insufficiency and activator of the integrated stress response (ISR), has emerged as a conserved regulator of the circadian clock in multiple organisms. The objective of this study was to examine diurnal patterns in hepatic ISR activation in the liver and whole body rhythms in metabolism. We hypothesized that GCN2 activation cues hepatic ISR signaling over a natural 24-h feeding-fasting cycle. To address our objective, wild-type (WT) and whole body Gcn2 knockout (GCN2 KO) mice were housed in metabolic cages and provided free access to either a control or leucine-devoid diet (LeuD) for 8 days in total darkness. On the last day, blood and livers were collected at CT3 (CT = circadian time) and CT15. In livers of WT mice, GCN2 phosphorylation followed a diurnal pattern that was guided by intracellular branched-chain amino acid concentrations (r2 = 0.93). Feeding LeuD to WT mice increased hepatic ISR activation at CT15 only. Diurnal oscillations in hepatic ISR signaling, the hepatic transcriptome including lipid metabolic genes, and triglyceride concentrations were substantially reduced or absent in GCN2 KO mice. Furthermore, mice lacking GCN2 were unable to maintain circadian rhythms in whole body energy expenditure, respiratory exchange ratio, and physical activity when fed LeuD. In conclusion, GCN2 activation functions to maintain diurnal ISR activation in the liver and has a vital role in the mechanisms by which nutrient stress affects whole body metabolism.NEW & NOTEWORTHY This work reveals that the eIF2 kinase GCN2 functions to support diurnal patterns in the hepatic integrated stress response during natural feeding and is necessary to maintain circadian rhythms in energy expenditure, respiratory exchange ratio, and physical activity during amino acid stress.

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GCN2 驱动肝脏综合应激反应的昼夜模式,并在氨基酸不足时维持全身代谢的昼夜节律。
昼夜节律紊乱与代谢性疾病发病风险的增加有关。一般控制非减压因子 2(GCN2)是氨基酸不足的主要传感器和综合应激反应(ISR)的激活因子,已成为多种生物中昼夜节律的保守调节因子。本研究的目的是考察肝脏中肝脏 ISR 激活的昼夜模式和全身代谢节律。我们假设 GCN2 的激活会在自然的 24 小时进食禁食周期中提示肝脏 ISR 信号转导。为了实现我们的目标,我们将野生型(WT)和全身Gcn2基因敲除(GCN2 KO)小鼠饲养在代谢笼中,让它们在完全黑暗的环境中自由摄入对照组或亮氨酸-去氧饮食(LeuD)8天。最后一天,在昼夜节律时间(CT)3和CT15采集血液和肝脏。在 WT 小鼠肝脏中,GCN2 磷酸化遵循细胞内支链氨基酸浓度引导的昼夜模式(r2=0.93)。给 WT 小鼠喂食 LeuD 只增加了 CT15 的肝 ISR 激活。在 GCN2 KO 小鼠中,肝脏 ISR 信号的昼夜振荡、包括脂质代谢基因在内的肝脏转录组以及甘油三酯浓度都大大降低或消失。此外,缺乏 GCN2 的小鼠在喂食 LeuD 时无法维持全身能量消耗、呼吸交换比和体力活动的昼夜节律。总之,GCN2 的激活功能可维持肝脏中昼夜节律的 ISR 激活,并在营养压力影响全身代谢的机制中发挥重要作用。
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来源期刊
CiteScore
9.80
自引率
0.00%
发文量
98
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
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