Systemic oscillator-driven and nutrient-responsive hormonal regulation of daily expression rhythms for gluconeogenic enzyme genes in the mouse liver.
Systemic oscillator-driven and nutrient-responsive hormonal regulation of daily expression rhythms for gluconeogenic enzyme genes in the mouse liver.
复制标题
系统振荡器驱动和营养响应的激素对小鼠肝脏中糖异生酶基因的日常表达节律的调节。
DOI：
10.1080/07420528.2019.1570246
复制
发表时间：
2019
影响因子：
2.8
通讯作者：
Takiguchi M.
中科院分区：
文献类型：
--
作者：
Taira A;Arita E;Matsumoto E;Oohira A;Iwase K;Hiwasa T;Yokote K;Shibata S;Takiguchi M.
糖异生是从氨基酸等底物合成新的葡萄糖，当葡萄糖缺乏时，这是至关重要的一天营养波动。因此，肝糖异生酶的基因表现出日常的表达节律，其在营养变化下的详细调控仍然难以捉摸。作为第一步，我们对小鼠肝脏中磷酸烯醇式丙酮酸羧激酶(PEPCK)、胞浆形式(Pck 1)、葡萄糖-6-磷酸酶(G6Pase)、催化亚基(G6pc)和酪氨酸氨基转移酶(Tat)等糖异生酶基因的日常表达谱进行了系统的研究。在标准饮食中，这些基因的mRNA水平显示出强健的每日节律，在昼夜摄食/禁食(清醒/睡眠)周期的睡眠-禁食后期有一个高峰或上升阶段。节律性在恒定的黑暗中保持，通过长时间的禁食来调节，通过时钟突变来减弱，并携带到不同的光周期和限时摄食中。这些结果与糖异生酶基因受内在昼夜节律振荡器控制的观点是一致的，内在昼夜节律振荡器受光/暗周期的影响，进而参与摄食/禁食周期，并驱动系统信号通路，如下丘脑-垂体-肾上腺轴。另一方面，限时喂养也表明，当摄取时间表与光/暗周期分开时，可以作为糖异生酶基因日常表达节律的独立夹带者。此外，营养变化极大地改变了基因的表达谱。除了长时间的禁食，高脂肪饮食和高碳水化合物(无蛋白质)饮食还导致了基因日常表达节律的改变，糖调节激素如皮质酮、胰高血糖素和胰岛素及其调节剂包括Ghrelin、瘦素、抵抗素、葡萄糖依赖的胰岛素样多肽(GIP)和胰高血糖素样肽-1(GLP-1)的图谱发生了典型的变化。值得注意的是，在醒食期，高蛋白(60%酪蛋白或大豆蛋白)日粮非典型地激活了糖异生酶基因，伴随着胰高血糖素的反常上调，这经常与其他体液因素形成关联网络。基于这些结果，我们认为糖异生酶基因的日常表达节律受系统振荡器驱动和营养响应激素的控制。
Gluconeogenesis isde novoglucose synthesis from substrates such as amino acids and is vital when glucose is lacking in the diurnal nutritional fluctuation. Accordingly, genes for hepatic gluconeogenic enzymes exhibit daily expression rhythms, whose detailed regulations under nutritional variations remain elusive. As a first step, we performed general systematic characterization of daily expression profiles of gluconeogenic enzyme genes for phosphoenolpyruvate carboxykinase (PEPCK), cytosolic form (Pck1), glucose-6-phosphatase (G6Pase), catalytic subunit (G6pc), and tyrosine aminotransferase (TAT) (Tat) in the mouse liver. On a standard diet fedad libitum, mRNA levels of these genes showed robust daily rhythms with a peak or an elevation phase during the late sleep-fasting period in the diurnal feeding/fasting (wake/sleep) cycle. The rhythmicity was preserved in constant darkness, modulated with prolonged fasting, attenuated byClockmutation, and entrained to varied photoperiods and time-restricted feedings. These results are concordant with the notion that gluconeogenic enzyme genes are under the control of the intrinsic circadian oscillator, which is entrained by the light/dark cycle, and which in turn entrains the feeding/fasting cycle and also drives systemic signaling pathways such as the hypothalamic-pituitary-adrenal axis. On the other hand, time-restricted feedings also showed that the ingestion schedule, when separated from the light/dark cycle, can serve as an independent entrainer to daily expression rhythms of gluconeogenic enzyme genes. Moreover, nutritional changes dramatically modified expression profiles of the genes. In addition to prolonged fasting, a high-fat diet and a high-carbohydrate (no-protein) diet caused modification of daily expression rhythms of the genes, with characteristic changes in profiles of glucoregulatory hormones such as corticosterone, glucagon, and insulin, as well as their modulators including ghrelin, leptin, resistin, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1). Remarkably, high-protein (60% casein or soy-protein) diets activated the gluconeogenic enzyme genes atypically during the wake-feeding period, with paradoxical up-regulation of glucagon, which frequently formed correlation networks with other humoral factors. Based on these results, we propose that daily expression rhythms of gluconeogenic enzyme genes are under the control of systemic oscillator-driven and nutrient-responsive hormones.