生物节律与肝脏能量代谢

生物节律起源于生物钟,是机体为适应外界环境的昼夜变化而进化成的一种内在变化节律.在其影响下,哺乳动物具有了明显的进食和禁食周期,产生了营养物质供需的节律性变化.近年来,大量研究表明生物节律与机体代谢有着紧密联系,而肝脏作为机体的代谢中枢,其功能必然受到昼夜节律的影响.随着现代社会节奏的加快,熬夜、轮班、快餐等生活方式打乱了机体原本节律,导致肝脏相关的代谢性疾病发病率大大增加,而昼夜节律的紊乱又可促进这些疾病的发生、发展,并影响其预后和转归.本文就肝脏生物钟基因的功能与糖、脂质、胆汁酸、蛋白质等代谢物质间的关系展开综述.     

昼夜节律变化对动脉粥样硬化形成的影响及其相关通路的研究进展

地球上几乎所有的生命都存在昼夜节律,控制昼夜节律的生物钟具有重要的生理功能,同时也是疾病的重要调节器。昼夜节律与动脉粥样硬化关系密切。研究表明受损的生物钟会影响造血过程和糖脂代谢,并改变局部斑块病变中的细胞功能。在分子水平上,昼夜节律可以通过Toll样受体(TLR)通路调节动脉粥样硬化炎症状态和血管重塑,通过蛋白激酶B(Akt)通路改善内皮功能和胰岛素信号传导,并通过CCL2-CCR2信号轴影响单核细胞的招募与淋巴细胞的活化。本篇综述讨论了动脉粥样硬化中昼夜节律的作用及分子机制,以及动脉粥样硬化与生物钟系统的联系。     

昼夜节律与胃肠道动力及肠道菌群的关系

昼夜节律是调节机体行为、生理、生物化学的24 h模式,机体的昼夜节律依赖于内源性的计时机制——生物钟。胃肠道与其他器官、系统一样,受24 h昼夜节律的调控。昼夜节律影响着胃肠道的许多功能,包括胃酸分泌、小肠营养吸收、结肠运动及肠道菌群。昼夜节律基因的表达,有助于调节胃肠道运动以及肠道内微生物群。该文就昼夜节律与胃肠动力、肠道菌群之间的关系作一综述。     

应重视代谢压力与胰岛β细胞代偿性增殖研究

近年来全球糖尿病患病率迅速增加,与超重和肥胖人群数量的急剧增加密切相关.肥胖患者体内存在明显的胰岛素抵抗,胰岛β细胞代偿性增殖,分泌大量胰岛素以维持血糖稳定.当胰岛β细胞失去代偿能力,即发生糖尿病.关于胰岛β细胞失代偿机制,已有大量研究,包括糖毒性、脂毒性等.显然,胰岛β细胞从代偿性增殖到失代偿是一个连续的变化过程,肥胖等胰岛素抵抗状态下胰岛β细胞代偿性增殖机制尤其不清楚.肥胖患者体内聚积的大量脂肪组织,及其脂代谢、氨基酸代谢和糖代谢异常形成的代谢压力,与胰岛β细胞增殖的关系也十分密切.本文就代谢压力下胰岛β细胞的代偿性增殖及其机制作一简要评述.     

类胰蛋白酶与代谢综合征

代谢综合征是心血管疾病的多种代谢危险因素在个体内集结的状态,主要包括肥胖、糖尿病或糖调节受损、血脂紊乱以及高血压.近来研究发现,代谢综合征的发病与机体慢性炎性反应状态相关.类胰蛋白酶是肥大细胞中含量最丰富的颗粒蛋白,也是一种重要的炎性介质,它可通过促进炎性反应细胞的聚集、细胞凋亡、新生血管形成、基质蛋白重塑等多种机制参与代谢综合征的发生与发展.     

Bmal1与心血管疾病关系的研究进展

昼夜节律是最常见的一种生物节律,在哺乳动物中,许多行为和生理过程都表现出近似24 h为周期的昼夜节律变化,昼夜节律发生的物质基础是分子计时器,即生物钟〔1〕.昼夜节律生物钟属于生物体内时间调控系统,是机体为了更好适应生存环境,在进化过程中自然条件下产生的〔2〕.昼夜节律分子反馈环路的核心部分是Clock/Bmal1组成...     

脂肪固有免疫细胞与胰岛素抵抗

胰岛素抵抗是指外周组织对胰岛素敏感性及反应性降低,肥胖是胰岛素抵抗的主要原因.近年来研究显示,脂肪组织内的炎性反应状态与胰岛素抵抗及2型糖尿病等代谢疾病之间存在密切关系,而脂肪组织中的巨噬细胞、肥大细胞、中性粒细胞、树突状细胞、嗜酸性粒细胞以及自然杀伤T细胞等多种固有免疫细胞通过活化和释放炎性反应介质,参与炎性反应,从而促进机体胰岛素抵抗的形成.进一步深入阐明固有免疫细胞在脂肪组织炎性反应和胰岛素抵抗方面的作用,可以为糖尿病基础研究和治疗提供新的方向和思路.     

引起2型糖尿病的那些因素

2型糖尿病的病因和发病机制目前尚不明确会诊其显著你们的病理生理学特征为胰岛β细胞功能缺陷所导致的胰岛素分泌减少(或相对减少)或胰岛素抵抗所导致的胰岛素在机体内调控葡萄糖代谢关心能力的下降或两者共同存在。那么哪些因素会引起2型糖尿病呢?肥胖肥胖者为什么容易患糖尿病呢?医学研究者认为这与脂肪细胞膜上胰岛素受体数目的减少和胰岛素受体对胰岛素的亲和力下降等因素有关。     

生物钟节律紊乱与高血压

生物钟蛋白参与许多重要生理过程的调节, 包括血压。核心生物钟基因的缺失或突变可造成血压水平升高以及血压节律紊乱, 加重血管功能损伤, 最终导致缺血性卒中的发生和发展以及转归不良。文章对生物钟节律的分子机制、生物钟基因与血压调控机制之间的联系、昼夜节律紊乱在高血压发生发展中的作用机制以及血压节律紊乱与卒中之间的关系进行了综述。     

昼夜节律紊乱与心脑血管疾病

昼夜节律参与调节多种生理、心理和行为变化,是生命活动的本质特性之一。昼夜节律的产生和维持依赖于多种时钟基因。研究表明,昼夜节律紊乱与心脑血管疾病的发生、发展存在密切的联系,表现在:(1)时钟基因广泛表达于心脑血管系统,并发挥重要的调节功能;(2)心率、血压、血儿茶酚胺水平等心脑血管系统核心指标均表现出昼夜节律变化;(3)心脑血管疾病的发病频率随时间昼夜波动;(4)肥胖、糖尿病、代谢综合征等心脑血管疾病相关病症与时钟基因多态性密切相关;(5)时钟基因对于血管内皮的再生和功能至关重要。该文结合最新研究进展阐述昼夜节律紊乱与心脑血管疾病的相关性,并探讨其可能的机制。     

Plasminogen Activator Inhibitor-1 and the Circadian Clock in Metabolic Disorders

Plasma PAI-1 levels robustly fluctuate in a circadian manner and consequently contribute to hypofibrinolysis during the early morning. The circadian expression of PAI-1 gene is thought to be directly regulated by the circadian clock proteins such as CLOCK and BMAL1/BMAL2 which drive the endogenous biological clock. Plasma PAI-1 levels are increased in the beginning of the active phase in both diurnal humans and in nocturnal rodents, suggesting that the rhythmic PAI-1 expression is commonly indispensable for organisms. A series of our recent studies revealed that circadian clock proteins are important for hypofibrinolysis induced by metabolic disorders such as obesity and diabetes.     

Molecular mechanisms interlinking biological clock and diabetes mellitus: Effective tools for better management

Background and aimAdvances in circadian biology have delineated the link between perturbed biological clock and metabolic diseases. Circadian disturbances are associated with the onset, progression and severity of diabetes mellitus.MethodsWe conducted a literature survey using the key terms - circadian, diabetes, circadian and diabetes, clock genes and diabetes, chronotherapy and peripheral clocks in science direct, PubMed, Google, and Embase till August 23, 2021.ResultsMisalignment between peripheral clocks located in pancreas, intestine, liver, adipose tissue and skeletal muscle and with the central oscillator alters the secretion of insulin, incretins, adipokines and soluble factors resulting in the derangement of metabolism leading to chronic hyperglycemia.ConclusionManagement of circadian health restores glucose homeostasis confirming that chronotherapy will help in the management of diabetes mellitus. Further, administration of circadian clock modifiers has proved potential therapeutic agents to treat diabetes mellitus. The aim of the review is to highlight the molecular mechanisms linking biological clock and diabetes mellitus and how they are useful for effective management of the disease.     

High-fat diet delays and fasting advances the circadian expression of adiponectin signaling components in mouse liver

The circadian clock controls energy homeostasis by regulating circadian expression and/or activity of enzymes involved in metabolism. Disruption of circadian rhythms may lead to obesity and metabolic disorders. We tested whether the biological clock controls adiponectin signaling pathway in the liver and whether fasting and/or high-fat (HF) diet affects this control. Mice were fed low-fat or HF diet and fasted on the last day. The circadian expression of clock genes and components of adiponectin metabolic pathway in the liver was tested at the RNA, protein, or enzyme activity level. In addition, serum levels of glucose, adiponectin, and insulin were measured. Under low-fat diet, adiponectin signaling pathway components exhibited circadian rhythmicity. However, fasting and HF diet altered this circadian expression; fasting resulted in a phase advance, and HF diet caused a phase delay. In addition, adenosine monophosphate-activated protein kinase levels were high during fasting and low during HF diet. Changes in the phase and daily rhythm of clock genes and components of adiponectin signaling pathway as a result of HF diet may lead to obesity and may explain the disruption of other clock-controlled output systems, such as blood pressure and sleep/wake cycle, usually associated with metabolic disorders.     

动脉粥样硬化危险因素衰老、肥胖、生物钟紊乱与核糖体新生的研究进展

动脉粥样硬化是心脑血管疾病的主要原因,可能由吸烟、高血压、衰老、肥胖、生物钟紊乱等多因素导致。核糖体作为蛋白质合成的分子机器,维持细胞内蛋白质稳态。文章聚焦于衰老、肥胖和生物钟紊乱对动脉粥样硬化的影响,以及与核糖体新生的关系,为动脉粥样硬化的机制研究和防治提供理论支持。     

The clock gene Rev-erbα regulates pancreatic β-cell function: modulation by leptin and high-fat diet

Disturbances of circadian rhythms have been associated with obesity and type 2 diabetes. The nuclear receptor Rev-erbα was suggested to link circadian rhythms and metabolism in peripheral tissues. The aim of the present study was to dissect the role of this clock gene in the pancreatic β-cell function and to analyze whether its expression is modulated by leptin and diet-induced obesity. To address the function of Rev-erbα, we used small interfering RNA in mouse islet cells and in MIN-6 cells. Cell proliferation was measured by bromodeoxyuridine incorporation, apoptosis by the terminal deoxynucleotidyl transferase dUTP nick end labeling technique, insulin secretion by RIA, and gene expression by RT-PCR. Pancreatic islets were isolated at different zeitgeber times 0, 6, and 12 after 6 wk of high-fat diet treatment, and then gene expression and insulin secretion were determined. Rev-erbα down-regulation by small interfering RNA treatment in islet cells and MIN-6 cells impaired glucose-induced insulin secretion, decreased the expression of key lipogenic genes, and inhibited β-cell proliferation. In vivo and in vitro leptin treatment increased Rev-erbα expression in isolated islets through a MAPK pathway. High-fat diet treatment disrupted the circadian Rev-erbα gene expression profile along with insulin secretion, indicating an important role of this clock gene in β-cell function. These results indicate that the clock gene Rev-erbα plays multiple functions in the pancreatic β-cell. Although the increase in Rev-erbα expression may promote β-cell adaptation in different metabolic situations, its deregulation may lead to altered β-cell function.     

The Role of Circadian Rhythms in the Hypertension of Diabetes Mellitus and the Metabolic Syndrome

Purpose of the Review

Cellular circadian clocks regulate physiological functions during day and night. It has been convincingly demonstrated that hypertension in patients suffering from diabetes mellitus or metabolic syndrome is characterized in most cases by a disturbed 24-h profile resulting in a nondipper pattern. We consider possible correlation between biological clocks and symptoms of the metabolic syndrome.

Recent Findings

Changes in circadian clock function have been linked to metabolic disorders in genome-wide association studies. Epidemiological studies have shown that a loss of nocturnal decline in blood pressure increases the risk of cardiovascular morbidity and mortality and end-organ damage. Looking at clock genes, however, there is no obvious association between symptoms of diabetes or metabolic syndrome and clock gene expression.

Summary

Emerging data suggest that circadian rhythm disruption is a risk factor for metabolic and cardiovascular disorders, while disease feedback on clock function is limited.