Interactions between sleep, stress, and metabolism: From physiological to pathological conditions
睡眠，压力和新陈代谢之间的相互作用：从生理到病理条件

Abstract 摘要

1. Introduction 1.导言 

Sleep and stress interact in a bidirectional fashion, sharing multiple pathways that affect the central nervous system (CNS) and metabolism, and may constitute underlying mechanisms responsible in part for the increasing prevalence of metabolic disorders such as obesity and diabetes [1]. Hormones like melatonin and others from the hypothalamic–pituitary–adrenal (HPA) axis modulate the sleep–wake cycle, while its dysfunction can disrupt sleep. In turn, sleep loss influence the HPA axis, leading to hyperactivation [2]. In the first part of this paper, we focus on the definitions of sleep and the HPA axis, and the relationship between sleep and stress. In the second part, we review the effects of sleep and stress on the metabolism, addressing mainly sleep deprivation, circadian alterations, and key sleep and stress disorders. Finally, we connected these topics to provide a better understanding of the intrinsic relationship between sleep, stress and metabolism, and suggest possible targets for future intervention.
睡眠和压力以双向方式相互作用，共享影响中枢神经系统（CNS）和代谢的多个途径，并且可能构成部分导致肥胖和糖尿病等代谢性疾病患病率增加的潜在机制[1]。褪黑激素和其他来自下丘脑-垂体-肾上腺（HPA）轴的激素调节睡眠-觉醒周期，而其功能障碍可能会扰乱睡眠。反过来，睡眠不足会影响HPA轴，导致过度激活[2]。在本文的第一部分中，我们重点介绍了睡眠和HPA轴的定义，以及睡眠和压力之间的关系。在第二部分中，我们回顾了睡眠和压力对新陈代谢的影响，主要涉及睡眠剥夺，昼夜节律改变，以及关键的睡眠和压力障碍。 最后，我们将这些主题联系起来，以更好地了解睡眠，压力和代谢之间的内在关系，并为未来的干预提出可能的目标。

The secretory activity of the HPA axis follows a distinct 24 h pattern. CRH is released in a circadian-dependent and pulsatile manner from the parvocellular cells of the PVN [3]. In fact, the circadian rhythm of cortisol secretion derives from the connection between the PVN and the central pacemaker, the suprachiasmatic nucleus (SCN) [4]. The close proximity of AVP-containing SCN nerve endings near CRH-containing neurons in the PVN suggests that via this projection circadian information is imprinted onto the HPA-axis [5]. Typically, the nadir (time point with the lowest concentration) for cortisol occurs near midnight. Then, cortisol levels increase 2–3 h after sleep onset, and keep rising into to the waking hours. The peak happens in the morning at about 9 a.m. [4]. Along the day, there is a progressive decline that is potentiated by sleep, until it reaches the nadir and the quiescent period (Fig. 1). In general, 3 main pathways are essential for biological clock function: the input (zeitgebers, retina) → SCN circadian pacemaker (as clock genes, neurotransmitters, peptides) → output (pineal melatonin synthesis, thermoregulation, hormones). Then, these factors interact with the sleep–wake cycle to modulate, for example, sleep propensity and sleep architecture, and influence behavior, performance or hormonal output such as cortisol [4].
HPA轴的分泌活动遵循一个独特的24小时模式。CRH以昼夜节律依赖性和脉冲方式从PVN的小细胞释放[3]。事实上，皮质醇分泌的昼夜节律来自PVN和中央起搏器，视交叉上核（SCN）之间的联系[4]。PVN中含有CRH的神经元附近含有AVP的SCN神经末梢的紧密接近表明，通过这种投射，昼夜节律信息被印记到HPA轴上[5]。通常，皮质醇的最低点（浓度最低的时间点）发生在午夜附近。然后，皮质醇水平在睡眠开始后2-3小时增加，并持续上升到清醒时间。高峰发生在上午9点左右[4]。沿着一天的时间，睡眠会增强这种下降，直到达到最低点和静止期（图1）。 一般来说，生物钟功能有3条主要途径：输入（授时器、视网膜）→ SCN昼夜节律起搏器（作为时钟基因、神经递质、肽）→输出（松果体褪黑激素合成、体温调节、激素）。然后，这些因素与睡眠-觉醒周期相互作用，以调节例如睡眠倾向和睡眠结构，并影响行为，表现或激素输出，如皮质醇[4]。

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Fig. 1  图1

24-h individual cortisol profile showing the minimum (nadir), the maximum (acrophase), the onset of the circadian rise, and the amplitude of the cortisol profile. After a nadir during the early night, there is an important rise in ACTH and cortisol in the late night, reaching a peak near the awakening time, driven by circadian oscillators, such as sleep.
24小时个体皮质醇曲线，显示皮质醇曲线的最小值（最低值）、最大值（峰值）、昼夜节律上升的开始和振幅。在深夜达到最低点后，ACTH和皮质醇在深夜有一个重要的上升，在觉醒时间附近达到峰值，这是由昼夜节律振荡器（如睡眠）驱动的。

2. Disturbed or shifted sleep, sleep loss and HPA axis
2.睡眠紊乱或移位，睡眠丧失和HPA轴 

Many stressful situations, such as low socioeconomic status and chronic work overload, have been associated with a deficit in sleep duration and several neuroendocrine effects (for review, see [6]). Indeed, there is long-standing evidence of reciprocal interactions between the HPA axis and sleep regulation [7], which will be discussed below.
许多紧张的情况，如低社会经济地位和慢性工作超负荷，与睡眠时间不足和几种神经内分泌效应有关（综述见[6]）。事实上，有长期存在的证据表明HPA轴和睡眠调节之间存在相互作用[7]，这将在下面讨论。

Circadian misalignment affects sleep architecture and may also reduce total sleep time. Both advanced and delayed phases result in disruption of the normal phase relationship between SWS and REM sleep [8]. During the first day of an 8 h phase delay, profound disruptions in the 24 h cortisol rhythm were found, with a higher nadir value mediated by the lack of the inhibitory effects caused by sleep onset, and lower acrophase values due to the lack of the stimulatory effects of awakening, resulting in an overall 40% reduction in the rhythm [9]. Five days after the shift, the cortisol profile had adapted to the new schedule [9]. On the other hand, an advanced phase of 8 h had advanced the timing of the cortisol nadir by about 3 h and 20 min, with marked reduction in the quiescent period, and increased the rising phase of cortisol secretion by 3 h [10]. In this last case, no adaptation of the timing of the acrophase to the new schedule was observed. In summary, these studies confirm that the misalignment of the sleep–wake cycle has a negative impact on the stress system. Although it seems to be a short-term effect probably due to a biphasic pattern of the cortisol rise after the shift, it may also contribute to metabolic changes. Alterations of the HPA axis may play a causative role in sleep disorders such as insomnia. HPA axis dysfunction may be secondary to a clinical sleep disorder, such as obstructive sleep apnea (OSA), leading to other complications.
昼夜节律失调影响睡眠结构，也可能减少总睡眠时间。提前和延迟阶段都导致SWS和REM睡眠之间正常相位关系的破坏[8]。在8小时相位延迟的第一天，发现24小时皮质醇节律的严重中断，由于缺乏睡眠开始引起的抑制作用而介导的最低值较高，由于缺乏觉醒的刺激作用而导致的顶相值较低，导致节律总体降低40%[9]。在转换后的第五天，皮质醇曲线已经适应了新的时间表[9]。另一方面，8小时的提前阶段使皮质醇最低点的时间提前了约3小时20分钟，静止期显著缩短，皮质醇分泌的上升阶段增加了3小时[10]。在最后一种情况下，没有观察到顶相的时间适应新的时间表。 总之，这些研究证实了睡眠-觉醒周期的失调对压力系统有负面影响。尽管这似乎是一种短期影响，可能是由于转变后皮质醇上升的双相模式，但它也可能导致代谢变化。HPA轴的改变可能在睡眠障碍如失眠中起致病作用。HPA轴功能障碍可能继发于临床睡眠障碍，如阻塞性睡眠呼吸暂停（OSA），导致其他并发症。

Insomnia is a sleep disorder characterized by difficulties in falling or staying asleep or having restorative sleep, associated with daytime impairment or distress [11]. Despite the relationship between sleep and the HPA axis, little is known about the neurobiological basis of this sleep disorder and its link with HPA axis activation. One study did not show any significant differences in urinary cortisol between control and poor sleepers [12]. However, another study presented a positive correlation between polysomnographic indices of sleep disturbance and urinary free cortisol in adults with insomnia [13]. Patients with insomnia without depression do present high levels of cortisol, mainly in the evening and at sleep onset, suggesting that, rather than the primary cause of insomnia, the increase in cortisol may be a marker of CRH and norepinephrine activity during the night [14]. Preceding evening cortisol levels are correlated with the number of the following night׳s nocturnal awakenings, independent of insomnia [15]. However, excessive activation of the HPA axis induces sleep fragmentation [16], while the sleep fragmentation increases cortisol levels [15], suggesting that the HPA axis may contribute to the initiation as well as the perpetuation of chronic insomnia [15]. There is still debate whether the activation of the HPA axis found in insomnia is secondary to sleep loss or a marker of CRH activity.
失眠是一种睡眠障碍，其特征是入睡或保持睡眠或恢复性睡眠困难，与日间损害或痛苦相关[11]。尽管睡眠和HPA轴之间的关系，很少有人知道这种睡眠障碍的神经生物学基础及其与HPA轴激活的联系。一项研究显示，控制组和睡眠不佳者之间的尿皮质醇没有任何显著差异[12]。然而，另一项研究显示，失眠成年人睡眠障碍的多导睡眠图指数与尿游离皮质醇呈正相关[13]。没有抑郁症的失眠患者确实存在高水平的皮质醇，主要是在晚上和入睡时，这表明皮质醇的增加可能是CRH和去甲肾上腺素在夜间活动的标志物，而不是失眠的主要原因[14]。 前一天晚上的皮质醇水平与第二天晚上夜间醒来的次数相关，与失眠无关[15]。然而，HPA轴的过度激活会导致睡眠片段化[16]，而睡眠片段化会增加皮质醇水平[15]，这表明HPA轴可能导致慢性失眠的发生和持续[15]。失眠症中HPA轴的激活是继发于睡眠不足还是CRH活性的标志，目前仍有争议。

OSA is a common sleep disordered breathing, characterized by recurrent apneas (complete breathing cessation) or hypopneas (shallow breathing), upper airway constriction, hypoxemia, hypercapnia, autonomic activation, and EEG arousal and sleep fragmentation, leading to daytime fatigue and sleepiness [17]. As nocturnal awakening is associated with pulsatile cortisol release and autonomic activation, we can expect OSA to lead to HPA axis activation through the same mechanisms involved in arousal and sleep fragmentation [4]. However, the studies to date are contradictory. Some have shown that continuous positive airway pressure (CPAP) therapy for OSA does not lower cortisol while the acute withdrawal of CPAP does not change cortisol levels [18]. On the other hand, other authors have demonstrated that CPAP does reverse hypercortisolemia [19]. A systematic review revealed that only 2 studies showed statistically significant differences in cortisol levels after CPAP treatment [20].
OSA是一种常见的睡眠呼吸障碍，其特征为反复呼吸暂停（完全呼吸停止）或呼吸不足（浅呼吸）、上气道收缩、低氧血症、高碳酸血症、自主神经激活以及EEG觉醒和睡眠片段化，导致日间疲劳和嗜睡[17]。由于夜间觉醒与脉动性皮质醇释放和自主神经激活相关，我们可以预期OSA通过与觉醒和睡眠片段化相同的机制导致HPA轴激活[4]。然而，迄今为止的研究是相互矛盾的。一些研究表明，持续气道正压通气（CPAP）治疗OSA不会降低皮质醇，而CPAP的急性停药不会改变皮质醇水平[18]。另一方面，其他作者已经证明CPAP确实可以逆转高皮质醇血症[19]。一项系统综述显示，只有2项研究显示CPAP治疗后皮质醇水平存在统计学显著差异[20]。

Elevated cortisol levels were reported in patients with OSA by some studies [21], but not in others [22]. Responsiveness of ACTH to CRH administration was much higher in obese patients with OSA, possibly due to alterations in the central control of ACTH secretion and impairment in the negative feedback of glucocorticoids [23]. A recent study showed that serum basal and peak cortisol levels were lower in OSA patients when compared to the control group during 1 μg ACTH and glucagon stimulation tests, showing an association between OSA and hypocortisolemia in the morning with reduced responses to ACTH and glucagon stimulation tests [24]. Many of the discrepancies observed in the literature are reflective of methodological differences. The majority of studies are limited by assessment of cortisol at a single time point. The available studies do not provide clear evidence regarding whether OSA is associated with alterations in cortisol levels or that treatment with CPAP changes cortisol levels. Methodological concerns such as infrequent sampling, failure to match comparison groups on demographic factors known to impact cortisol levels (age, body mass index etc.), and inconsistent control of confounding factors may have limited the findings. However, there is evidence that excessive HPA axis activation may be a result from sleep loss, hypoxemia, and autonomic activation, playing an important role in the metabolic alterations arising from OSA [17].
一些研究报告了OSA患者皮质醇水平升高[21]，但其他研究没有[22]。在患有OSA的肥胖患者中，ACTH对CRH给药的反应性更高，这可能是由于ACTH分泌的中枢控制改变和糖皮质激素负反馈受损[23]。最近的一项研究表明，在1 μg ACTH和胰高血糖素刺激试验期间，与对照组相比，OSA患者的血清基础和峰值皮质醇水平较低，表明OSA与早晨低皮质醇血症之间存在相关性，对ACTH和胰高血糖素刺激试验的反应降低[24]。文献中观察到的许多差异反映了方法上的差异。大多数研究受限于在单个时间点对皮质醇的评估。 现有的研究并没有提供明确的证据，说明OSA是否与皮质醇水平的改变有关，或者CPAP治疗是否会改变皮质醇水平。方法学问题，如采样频率不高，未能在已知影响皮质醇水平的人口统计学因素（年龄、体重指数等）上匹配比较组，对混杂因素的不一致控制可能限制了研究结果。然而，有证据表明，过度的HPA轴激活可能是睡眠不足、低氧血症和自主神经激活的结果，在OSA引起的代谢改变中起重要作用[17]。

Many studies have shown increase in cortisol levels during the nighttime period of total sleep deprivation and in the prolonged wakefulness of the following day. This is likely a result of stress due to the effort of maintaining wakefulness, as high frequency EEG activity is correlated with indices of arousal and cortisol release [25], [26]. However, some authors also reported no change [27], [28] or a decrease in cortisol levels [29], [30] after 1 or more nights of sleep deprivation. These discrepancies seem to be influenced by insufficient frequency of blood sampling, small sample size, and by fatigue and sleepiness. In animals, however, the results are more consistent. Adult rats subject to paradoxical sleep deprivation during 96 h show increased levels of corticosterone, which are normalized after 48 h of sleep rebound [31]. Notwithstanding, it is important to consider that animal models do not accurately reflect human physiology; and thus, it is difficult to compare these results.
许多研究表明，在夜间完全睡眠剥夺期间以及第二天长时间清醒期间，皮质醇水平会增加。这可能是由于保持清醒的努力造成的压力的结果，因为高频EEG活动与唤醒和皮质醇释放的指数相关[25]，[26]。然而，一些作者也报告说，在一个或多个晚上的睡眠剥夺后，皮质醇水平没有变化[27]，[28]或下降[29]，[30]。这些差异似乎受到血液采样频率不足、样本量小以及疲劳和嗜睡的影响。然而，在动物身上，结果更加一致。在96小时内受到反常睡眠剥夺的成年大鼠显示皮质酮水平增加，在睡眠反弹48小时后恢复正常[31]。尽管如此，重要的是要考虑到动物模型不能准确反映人体生理学;因此，很难比较这些结果。

Studies using chronic protocols of sleep restriction, which model a widespread condition in modern society, have also addressed the role of HPA axis. The first study assessed the effect of 6 consecutive nights of 4 h in bed in young men, showing increased levels of cortisol in the afternoon and early evening, and a shorter quiescent period, with onset delayed by 1.5 h [16]. The rate of decrease of free cortisol in saliva was nearly 6 times slower in sleep restricted volunteers compared to fully rested condition. Notably, chronic short sleepers do present higher levels of cortisol compared to chronic long sleepers [32].
使用睡眠限制的慢性协议的研究，其模拟了现代社会中的普遍状况，也解决了HPA轴的作用。第一项研究评估了年轻男性连续6晚卧床4小时的影响，显示下午和傍晚皮质醇水平升高，静止期缩短，发作延迟1.5小时[16]。与完全休息的情况相比，睡眠受限的志愿者唾液中游离皮质醇的下降速度慢了近6倍。值得注意的是，与慢性长睡眠者相比，慢性短睡眠者的皮质醇水平确实更高[32]。

Sleep deprivation seems to be related to the elevation of cortisol, reflecting impairment of HPA axis regulation, and resulting in glucocorticoid overload, which can lead to large deleterious effects on the body. Moreover, there is an association between short sleep duration and higher risk of developing obesity and type II diabetes, suggesting the HPA axis hyperactivation as one of the mechanism involved in the metabolic consequences of sleep loss [33], [34].
睡眠剥夺似乎与皮质醇升高有关，反映HPA轴调节受损，并导致糖皮质激素超负荷，这可导致对身体的大的有害影响。此外，睡眠时间短与患肥胖症和II型糖尿病的风险较高之间存在关联，表明HPA轴过度激活是睡眠不足代谢后果的机制之一[33]，[34]。

3. Effects of glucocorticoids on sleep and metabolism
3.糖皮质激素对睡眠和代谢的影响 

Classic studies in rats and humans have demonstrated that exogenous CRH is able to modulate sleep by increasing EEG frequency and wakefulness and decreasing SWS [35], [36]. However, studies focused on the direct effects of glucocorticoids have shown that they increase time spent awake at the expense of REM sleep [37]. Other studies show that cortisol decreases SWS when MRs are activated, while dexamethasone increases awakening after activation of GRs [38]. The effects of both exogenous and endogenous glucocorticoids on sleep EEG depend on the type and location of the receptors activated (MR vs. GR), the dose of cortisol/corticosterone used, and the optimal cortisol levels to effect maximal nocturnal CRH suppression [4], [39]. Studies that have demonstrated decreases in SWS with elevated cortisol levels and total occupation of GR may be due to excessive GR activation in the amygdala. The effects are opposite to the known inhibitory action found in PVN and anterior pituitary, leading to positive feedback [39], [40]. However, the effects of glucocorticoids as well as CRH on REM are not well understood and most of them are contradictory [4].
大鼠和人类的经典研究表明，外源性CRH能够通过增加EEG频率和觉醒以及减少SWS来调节睡眠[35]，[36]。然而，针对糖皮质激素直接作用的研究表明，它们会以REM睡眠为代价增加清醒时间[37]。其他研究表明，皮质醇在MR激活时会降低SWS，而地塞米松在GR激活后会增加觉醒[38]。外源性和内源性糖皮质激素对睡眠EEG的影响取决于激活受体的类型和位置（MR与GR）、所用皮质醇/皮质酮的剂量以及实现最大夜间CRH抑制的最佳皮质醇水平[4]，[39]。研究表明，皮质醇水平升高和糖皮质激素受体完全占据的SWS减少可能是由于杏仁核中的糖皮质激素受体过度激活。 这种作用与PVN和垂体前叶中发现的已知抑制作用相反，导致正反馈[39]，[40]。然而，糖皮质激素以及CRH对REM的影响尚未得到很好的理解，其中大多数是相互矛盾的[4]。

Chronic exposure to excess glucocorticoids, such as occurs during diseases like Cushing׳s syndrome, can offer insight into the role of these hormones in sleep. For example, consistent alterations in polysomnographic recordings are reported in Cushing׳s syndrome, such as reduction of SWS, increased sleep latency, enhanced wake time, shortened REM latency, and elevated REM density, among others [17], reflecting the deleterious effects of glucocorticoid excess. Bierwolf and colleagues [41] have demonstrated that adrenal secretory activity starts predominantly during periods of NREM in both Cushing׳s and healthy patients, showing a link between pituitary–adrenal activity and the ultradian rhythmicity of NREM and REM sleep.
长期暴露于过量的糖皮质激素，例如在库欣氏综合征等疾病中发生的，可以深入了解这些激素在睡眠中的作用。例如，在库欣氏综合征中报告了多导睡眠图记录的一致改变，例如SWS减少、睡眠潜伏期增加、觉醒时间增加、REM潜伏期缩短和REM密度升高等[17]，反映了糖皮质激素过量的有害影响。Bierwolf及其同事[41]已经证明，在库欣综合征患者和健康患者中，肾上腺分泌活动主要在NREM期间开始，这表明垂体-肾上腺活动与NREM和REM睡眠的超昼夜节律性之间存在联系。

Reductions in sleep duration have become common due to the socioeconomic demands and opportunities in modern society [42]. In average, self-reported sleep time has decreased 1.5–2 h in the USA [43]. Quantitative alterations in sleep duration may impact the metabolic balance of the body, including control of body mass and food intake, glucose metabolism, and adipokine levels (for review, see [44]). In addition to the neurocognitive consequences of sleep loss, recent studies have been focused on the role of sleep in areas outside the brain, including other organs and physiological systems, such as the metabolism [45].
由于现代社会的社会经济需求和机会，睡眠时间的减少已经变得普遍[42]。在美国，自我报告的睡眠时间平均减少了1.5-2小时[43]。睡眠时间的定量改变可能会影响身体的代谢平衡，包括控制体重和食物摄入、葡萄糖代谢和脂肪因子水平（综述见[44]）。除了睡眠不足的神经认知后果外，最近的研究还集中在睡眠在大脑以外区域的作用，包括其他器官和生理系统，如新陈代谢[45]。

Many studies have shown an association between sleep duration and obesity both in adults and children, suggesting that short sleep duration may be a predictor of weight gain [46], [47], [48] and an important risk factor for development of insulin resistance, diabetes, and cardiovascular disease [16], [49], [50]. A meta-analysis revealed that each reduction of 1 h of sleep per day is associated with an increase of 0.35 kg m⁻² in body mass index (BMI) [51]. These observed changes due to sleep loss indicate a probable imbalance between food intake and energy expenditure caused by neuroendocrine alterations.
许多研究表明，睡眠时间与成人和儿童的肥胖之间存在关联，这表明睡眠时间短可能是体重增加的预测因素[46]，[47]，[48]以及胰岛素抵抗，糖尿病和心血管疾病发展的重要风险因素[16]，[49]，[50]。一项荟萃分析显示，每天睡眠时间每减少1小时，体重指数（BMI）就会增加0.35 kg m ⁻² [51]。这些观察到的变化，由于睡眠不足表明，可能是不平衡的食物摄入量和能量消耗所造成的神经内分泌的改变。

Naturally, sleep is a period of fasting. Glucose utilization by the brain is increased during REM sleep at the end of the night [52], leading to a negative energy balance in the body. However, sleep “resets” the metabolism and energy expenditure rates in the brain, giving effective and flexible control of energy expenditure under changing environmental pressures [53]. Much like sleep, hypothalamic control of metabolism is comprised by mutually inhibiting networks. The appetite-promoting neuropeptide Y (NPY) and agouti-related protein (AGRP) neurons mutually inhibit the appetite-suppressing pro-opiomelanocortin (POMC) and amphetamine-related transcript (CART) neurons. Both sets of neurons work as sensors of the circulating hormones leptin and ghrelin. Leptin is produced by adipose tissues and promotes satiety through inhibition of NPY/AGRP neurons and activation of POMC/CART neurons, with higher levels during sleep compared to awake states, independent of food intake [54]. Recent animal studies have also suggested that leptin participates in sleep regulation, reducing REM sleep and modulating SWS [55]. In turn, ghrelin is an appetite-stimulating hormone produced in the gut, which acts by inhibiting POMC/CART and activating NPY/AGRP. Like leptin, ghrelin has higher levels during sleep, which are followed by a decrease in the morning before the breakfast [56]. Current evidence indicates that ghrelin is also a sleep-promoting factor, able to induce SWS and stimulates GH secretion during the night [57], [58].
当然，睡眠是一段禁食的时间。大脑对葡萄糖的利用在夜间结束时的REM睡眠期间增加[52]，导致体内的负能量平衡。然而，睡眠“重置”大脑中的新陈代谢和能量消耗率，在不断变化的环境压力下有效和灵活地控制能量消耗。就像睡眠一样，下丘脑对新陈代谢的控制是由相互抑制的网络组成的。促进食欲的神经肽Y（NPY）和刺鼠相关蛋白（AGRP）神经元相互抑制食欲的阿黑皮素原（POMC）和苯丙胺相关转录物（CART）神经元。这两组神经元都作为循环激素瘦素和生长激素释放肽的传感器工作。瘦素由脂肪组织产生，并通过抑制NPY/AGRP神经元和激活POMC/CART神经元来促进饱腹感，与清醒状态相比，睡眠期间的水平更高，与食物摄入无关[54]。 最近的动物研究也表明，瘦素参与睡眠调节，减少REM睡眠和调节SWS [55]。反过来，ghrelin是一种在肠道中产生的食欲刺激激素，它通过抑制POMC/CART和激活NPY/AGRP起作用。像瘦素一样，ghrelin在睡眠期间的水平较高，然后在早餐前的早晨下降[56]。目前的证据表明，ghrelin也是一种促进睡眠的因子，能够诱导SWS并刺激GH在夜间分泌[57]，[58]。

Sleep curtailment is able to change food intake as a result of decreased secretion of leptin [59], [60], [61] and increased secretion of ghrelin [49], [59], [62], which leads to increased food intake [49]. Two consecutive nights of sleep restriction (4 h of time in bed) in young men were associated with a 28% increase in ghrelin and 18% reduction in leptin during the day, leading to increased hunger (24%) and appetite (23%), mostly for energy-rich foods with high carbohydrate content and low nutritional quality, such as sweets, salty snacks and starchy foods [49]. Six consecutive nights of sleep restriction (4 h of time in bed) increased sympathetic nervous system activity, evening cortisol level and growth hormone, in addition to decreasing glucose effectiveness and the acute insulin response by 30% each, much like is found in non-insulin-dependent diabetes [16]. Buxton and colleagues [63] found that sleep restriction (5 h/night) for 1 week significantly reduced insulin sensitivity, although no correlation was observed with cortisol levels. In a protocol of 14 consecutive days of sleep restriction (5.5 h of time in bed) with ad libitum food intake, caloric consumption was increased during the night, when the individual would generally be sleeping, explaining in part the increased vulnerability for weight gain induced by sleep loss [64]. On the other hand, another study did not find differences in hunger ratings after 1 night of total sleep deprivation compared to 1 night of sleep recovery (8 h time in bed) both in men and women [65]. However, actual food intake was not measured in this study, and therefore it is unknown whether participants would or would not have actually increased their food intake during the day of total sleep deprivation compared to the day of sleep rebound [66]. Gonnissen and colleagues [67] evaluated the effect of sleep fragmentation during 8 h on subjective feelings of appetite in men. They did not find a significant reduction in total sleep duration, but rather a reduction in REM sleep and an increase in N2 sleep stage. The volunteers reported a greater desire to eat after the night of sleep fragmentation, suggesting that sleep quality may be more important than sleep duration for appetite regulation, although they did not measure food intake in this study [67].
[2019 - 05 - 19][2019 - 05][201年轻男性连续两晚的睡眠限制（卧床4小时）与白天生长激素释放肽增加28%和瘦素减少18%相关，导致饥饿感（24%）和食欲（23%）增加，主要是碳水化合物含量高和营养质量低的富含能量的食物，如糖果，咸零食和淀粉类食物[49]。连续六个晚上的睡眠限制（卧床4小时）增加了交感神经系统活动，夜间皮质醇水平和生长激素，除了降低葡萄糖有效性和急性胰岛素反应各30%之外，与非胰岛素依赖型糖尿病非常相似[16]。 Buxton及其同事[63]发现，睡眠限制（每晚5小时）1周可显著降低胰岛素敏感性，但与皮质醇水平无相关性。在一项连续14天的睡眠限制（卧床5.5小时）和随意进食的方案中，热量消耗在夜间增加，此时个体通常在睡觉，部分解释了睡眠不足引起的体重增加的脆弱性[64]。另一方面，另一项研究没有发现男性和女性在完全睡眠剥夺1晚后与睡眠恢复1晚（床上8小时）后的饥饿评分存在差异[65]。然而，在这项研究中没有测量实际的食物摄入量，因此不知道与睡眠反弹的当天相比，参与者在完全睡眠剥夺的当天是否会增加他们的食物摄入量[66]。 Gonnissen及其同事[67]评估了8小时内睡眠片段对男性食欲主观感觉的影响。他们没有发现总睡眠时间的显着减少，而是REM睡眠减少和N2睡眠阶段增加。志愿者报告说，在睡眠碎片化的夜晚之后，他们更想吃东西，这表明睡眠质量可能比睡眠时间对食欲调节更重要，尽管他们在这项研究中没有测量食物摄入量[67]。

Increasing specific clinical evidence has shown that sleep quality and metabolic-related systems are connected. For instance, 50–98% of patients with OSA are morbidly obese [6]. There is an association between OSA and type 2 diabetes [68]. Cross-sectional studies indicate that up to 30% of patients with OSA also present type 2 diabetes, while up to 86% of obese patients with type 2 diabetes have OSA [69], [70]. Strong evidence suggests that OSA may increase the risk of developing insulin resistance, glucose intolerance and diabetes [71]. Metabolic disorders and OSA share common pathogenic pathways, such as alterations in autonomic nervous system regulation, increased inflammatory activity, alterations in adipokine levels and endothelial dysfunction, which may be involved in the interplay between these conditions [71]. However, it is not well understood whether these effects are likely due to obesity. In this sense, a systematic review showed that the current literature does not support the hypothesis that OSA independently influences glucose metabolism [72]. The methodological quality varied a lot within the included studies, pointing to a need for more powerful, long-term randomized controlled trials defining changes of insulin resistance as primary endpoint [72].
越来越多的具体临床证据表明，睡眠质量和代谢相关系统是相互关联的。例如，50-98%的OSA患者是病态肥胖[6]。OSA与2型糖尿病之间存在关联[68]。横断面研究表明，高达30%的OSA患者也患有2型糖尿病，而高达86%的肥胖2型糖尿病患者患有OSA [69]，[70]。强有力的证据表明，OSA可能会增加胰岛素抵抗、葡萄糖耐受不良和糖尿病的风险[71]。代谢障碍和OSA具有共同的致病途径，例如自主神经系统调节的改变、炎症活性增加、脂肪因子水平的改变和内皮功能障碍，这些可能参与这些病症之间的相互作用[71]。然而，目前还不清楚这些影响是否可能是由于肥胖。 从这个意义上说，一项系统性综述表明，目前的文献不支持OSA独立影响葡萄糖代谢的假设[72]。纳入研究的方法学质量差异很大，表明需要更强大的长期随机对照试验，将胰岛素抵抗的变化定义为主要终点[72]。

Obesity is commonly associated with narcolepsy, a sleep disorder characterized by hypocretin (also called orexin) deficiency, excessive daytime sleepiness, and frequent sleep attacks during the day [73]. Narcoleptic patients often present an excess of fat storage in abdominal depots, metabolic alterations, and craving for food with a binge eating pattern [74], [75]. The responsiveness of orexin neurons to peripheral metabolic cues, such as leptin and glucose, and the dopaminergic reward system response suggest that both of these 2 neurons are related to the regulation of energy homeostasis and vigilance states [76]. The studies are limited and it is not clear if narcolepsy independently affects glucose metabolism. A recent case-control study showed no clinically relevant pathologic findings in the glucose metabolism of narcoleptic patients compared to weight matched controls [77]. On the other hand, Poli and colleagues showed that narcoleptic patients have higher BMIs and BMI-independent metabolic alterations, such as higher waist circumference, high-density lipoprotein cholesterol, and insulin resistance, compared to idiopathic hypersomnia patients [78]. Evidence has shown that continuous disruption of circadian rhythm in human shift workers is associated with weight gain, metabolic disturbances, type 2 diabetes, and cardiovascular diseases due to increases in postprandial glucose, insulin, cortisol, and mean arterial pressure and decreased 24 h leptin levels [45], [79], [80].
肥胖通常与发作性睡病有关，发作性睡病是一种睡眠障碍，其特征在于下丘脑泌素（也称为食欲素）缺乏、白天过度嗜睡和白天频繁的睡眠发作[73]。发作性睡病患者通常表现为腹部脂肪储存过多，代谢改变，以及对食物的渴望和暴食模式[74]，[75]。食欲素神经元对外周代谢线索（如瘦素和葡萄糖）的反应以及多巴胺能奖励系统反应表明，这两种神经元均与能量稳态和警惕状态的调节有关[76]。这些研究是有限的，它是不清楚，如果发作性睡病独立影响葡萄糖代谢。最近的一项病例对照研究显示，与体重匹配的对照组相比，发作性睡病患者的葡萄糖代谢没有临床相关的病理学发现[77]。 另一方面，Poli及其同事表明，与特发性睡眠过度患者相比，发作性睡眠患者具有更高的BMI和BMI非依赖性代谢改变，例如腰围更高，高密度脂蛋白胆固醇和胰岛素抵抗[78]。有证据表明，由于餐后葡萄糖、胰岛素、皮质醇和平均动脉压增加以及24小时瘦素水平降低，人类轮班工人昼夜节律的持续中断与体重增加、代谢紊乱、2型糖尿病和心血管疾病相关[45]，[79]，[80]。

Another relevant factor that contributes to the development of metabolic disturbances associated with sleep restriction is energy expenditure. Individuals who sleep less are more likely to experience fatigue and sleepiness during the day, which may discourage them from daytime physical activity and promote sedentary behaviors [81], [82]. However, the literature presents varied results, in part due to differences in sleep protocols, either total sleep deprivation [83], [84] or partial sleep restriction [85], [86], and measurement type (doubly-labeled water [86], [87], indirect calorimetry [84], metabolic chamber [83], [88], or actigraphy [85], [86]). The majority of studies have enrolled small samples with only young, normal-weight men [83], [84], [88]. Thus, more studies are necessary to determine if sleep duration does affect total energy expenditure and if there is difference between men and women, normal weight and overweight/obese, and young and older individuals. It is possible that improving physical activity could improve sleep, which in turn would impact other components of energy balance, since individual variability in sleep onset latency is reduced by regular physical activity [89].
另一个与睡眠限制相关的代谢紊乱的发展有关的因素是能量消耗。睡眠较少的人更容易在白天感到疲劳和困倦，这可能会阻碍他们白天的身体活动并促进久坐行为[81]，[82]。然而，文献呈现了不同的结果，部分原因是睡眠方案的差异，无论是完全睡眠剥夺[83]，[84]还是部分睡眠限制[85]，[86]，以及测量类型（双标记水[86]，[87]，间接量热法[84]，代谢室[83]，[88]或活动记录仪[85]，[86]）。大多数研究只招募了年轻、体重正常的男性[83]，[84]，[88]。因此，需要更多的研究来确定睡眠时间是否会影响总能量消耗，以及男性和女性，正常体重和超重/肥胖，以及年轻人和老年人之间是否存在差异。 改善身体活动可能会改善睡眠，这反过来又会影响能量平衡的其他组成部分，因为睡眠开始潜伏期的个体差异会通过定期的身体活动减少[89]。

Not only can sleep affect metabolism, but metabolic changes also can affect sleep architecture [73]. There is an association between late-night-snack intake and sleep patterns [56]. Rodents adjust their sleep onset to match food availability during their sleep–wake cycle [90]. Inversely, food restriction can increase sleep onset latency and reduce total SWS [91]. The common behavior of overeating during a period of sleep deprivation may be a physiological attempt to restore sleep, as it is known that higher food intake promotes sleep [92]. The impact of sleep duration on energy expenditure is less clear due to the multiple factors involved, such as sleeping metabolic rate, thermic effect of food, physical activity, non-exercise activity thermogenesis, etc. [66]. In summary, current literature shows a pattern of increased food intake during periods of sleep loss, mostly in lean and normal sleepers. To date, studies looking for the influence of sleep duration on energy expenditure have produced disparate results due to methodological issues. Due to individual variability, future research assessing whether improving physical activity would improve sleep is also desired for a better understanding.
睡眠不仅会影响新陈代谢，而且新陈代谢的变化也会影响睡眠结构[73]。睡眠与睡眠的关系[56]。啮齿动物在睡眠-觉醒周期中调整其睡眠开始以匹配食物可用性[90]。然而，食物限制可以增加睡眠开始潜伏期并减少总SWS [91]。在睡眠剥夺期间暴饮暴食的常见行为可能是恢复睡眠的生理尝试，因为众所周知，较高的食物摄入量促进睡眠[92]。由于涉及多种因素，如睡眠代谢率、食物的热效应、体力活动、非运动活动产热等，睡眠时间对能量消耗的影响不太清楚[66]。总之，目前的文献显示，在睡眠不足期间，食物摄入量增加，主要是在瘦人和正常睡眠者中。 迄今为止，由于方法问题，寻找睡眠时间对能量消耗影响的研究产生了不同的结果。由于个体差异，未来的研究评估是否改善身体活动会改善睡眠也需要更好的理解。

4. Stress and metabolism 4.压力和新陈代谢 

Similarly to sleep, stress is also connected to metabolism. Basal HPA axis activity seems to be dysregulated and overactive both in humans with diabetes and in animal models of type 1 and type 2 diabetes, underlining the neuroendocrine abnormalities common to diabetes-related risk factors such as depression, obesity, hypertension, and cardiovascular diseases [93], [94]. Exposure to stressful events leads to increased release of glucocorticoids by activation of the HPA axis [95]. Prolonged activation of the HPA axis may result in maladaptive changes [96], affecting puberty, stature, body composition, as well as leading to obesity, metabolic syndrome, and type 2 diabetes mellitus [97]. Excesses in glucocorticoids increase glucose and insulin and decrease adiponectin levels [98]. Stress exposure alters food intake [99], increasing or decreasing it, depending upon the type of stress [100]. For instance, Ely and colleagues [99] showed that rats subjected to repeated stress by restraint presented increased ingestion of sweet food, while models of chronic variable stress demonstrated a decrease in appetite for sweet food or palatable solutions [101]. There is evidence that glucocorticoids stimulate appetite [102] and increase body weight through the orexigenic effect of NPY [103], an effect that is inhibited by leptin and insulin [103]. Clinical studies also reveal high food consumption, specifically of palatable food, during periods of psychological stress [104]. The increase in palatable food intake is induced by glucocorticoids [105] and is associated with reward-based eating, as a way to reduce the stress response [106].
与睡眠类似，压力也与新陈代谢有关。基础HPA轴活动似乎在糖尿病患者和1型和2型糖尿病动物模型中失调和过度活跃，强调糖尿病相关风险因素常见的神经内分泌异常，如抑郁症，肥胖症，高血压和心血管疾病[93]，[94]。暴露于压力事件导致通过激活HPA轴增加糖皮质激素的释放[95]。HPA轴的长期激活可能导致适应不良的变化[96]，影响青春期、身高、身体组成，以及导致肥胖、代谢综合征和2型糖尿病[97]。糖皮质激素过量会增加葡萄糖和胰岛素，降低脂联素水平[98]。压力暴露会改变食物摄入量[99]，增加或减少它，这取决于压力的类型[100]。 例如，伊利及其同事[99]表明，通过束缚反复应激的大鼠表现出对甜食的摄入增加，而慢性可变应激模型表现出对甜食或可口溶液的食欲下降[101]。有证据表明，糖皮质激素刺激食欲[102]，并通过NPY的促食欲作用增加体重[103]，瘦素和胰岛素抑制这种作用[103]。临床研究也揭示了在心理压力期间的高食物消耗，特别是可口的食物[104]。可口食物摄入量的增加是由糖皮质激素引起的[105]，并与奖励性饮食有关，作为减少应激反应的一种方式[106]。

Although it appears that hypercortisolemia may contribute to the development of different features of metabolic syndrome, it is not clear in the literature whether glucocorticoids play a role in the pathogenesis of obesity. Some studies show that cortisol levels are not higher in obese subjects, and sometimes they are even lower than in lean subjects [107], [108]. This may be, at least in part, a consequence of enhanced cortisol clearance that is thought to accompany obesity, for instance, through increased activity of 5α-reductase in the liver [108]. Mean 24 h plasmatic ACTH levels were positively correlated with body mass index, reflecting increased hypothalamic drive and reduced negative feedback of cortisol in obesity [109].
虽然高皮质醇血症可能导致代谢综合征不同特征的发展，但文献中尚不清楚糖皮质激素是否在肥胖的发病机制中发挥作用。一些研究表明，皮质醇水平并不高于肥胖受试者，有时甚至低于瘦受试者[107]，[108]。这可能至少部分是皮质醇清除增强的结果，皮质醇清除被认为伴随肥胖，例如，通过增加肝脏中5α-还原酶的活性[108]。平均24小时血浆ACTH水平与体重指数呈正相关，反映了肥胖患者下丘脑驱动力增加和皮质醇负反馈减少[109]。

Other factors related to cortisol action are also determinants. In this sense, the local expression of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) plays a role in the relationship between cortisol, adiposity, and metabolic disease [110]. The enzyme 11β-HSD1, expressed in several peripheral tissues, such as liver ad adipose tissue, can modulate HPA axis activity, regenerating active cortisol from its inactive form intracellularly [111]. In humans, 11β-HSD1 expression is increased in subcutaneous adipose tissue from obese subjects compared to lean subjects [112], being stimulated by TNFα, leptin and adipokines [113], [114].
与皮质醇作用相关的其他因素也是决定因素。从这个意义上说，11β-羟基类固醇脱氢酶1（11β-HSD 1）的局部表达在皮质醇、肥胖和代谢疾病之间的关系中发挥作用[110]。在几种外周组织（如肝脏和脂肪组织）中表达的酶11β-HSD 1可调节HPA轴活性，在细胞内将其非活性形式的皮质醇再生为活性皮质醇[111]。在人体中，与瘦型受试者相比，受TNFα、瘦素和脂肪因子刺激，肥胖受试者皮下脂肪组织中11β-HSD 1表达增加[112][113]，[114]。

In the presence of insulin, cortisol promotes triglyceride accumulation, mainly in visceral adipocytes, thus leading to increased central adiposity. Masuzaki and colleagues have also demonstrated that overexpression of 11β-HSD1 in adipose tissue resulted in visceral obesity and metabolic syndrome in mice fed with a high-fat diet [115]. Adipose tissue that overexpressed 11β-HSD2, the enzyme that inactivates cortisol, protected mice from high-fat diet-induced obesity [116]. The modulation of 11β-HSD1 might be a promising therapeutic target for obesity and metabolic disturbances. Studies focusing the inhibition of 11β-HSD1 in animal models of diabetes and obesity have shown improvement of insulin resistance and glucose levels, beyond weight loss [117], [118].
在胰岛素存在下，皮质醇促进甘油三酯积累，主要在内脏脂肪细胞中，从而导致中心性肥胖增加。Masuzaki及其同事还证明，脂肪组织中11β-HSD 1的过表达导致高脂饮食喂养的小鼠内脏肥胖和代谢综合征[115]。过表达11β-HSD 2（使皮质醇失活的酶）的脂肪组织可保护小鼠免受高脂饮食诱导的肥胖[116]。调节11β-HSD 1可能是肥胖和代谢紊乱的一个有希望的治疗靶点。在糖尿病和肥胖症动物模型中重点抑制11β-HSD 1的研究显示，除体重减轻外，胰岛素抵抗和葡萄糖水平也得到改善[117]，[118]。

Dysregulation of the HPA axis has been associated with some eating disorders [119], [120], mainly due to changes in insulin, NPY levels, and other peptides implicated in food intake regulation that can be modulated by cortisol metabolism [112]. Food intake is stimulated by administration of glucocorticoid prednisone in healthy men [121], while diet influences cortisol metabolism, affecting the HPA axis and the reward circuitry for palatable foods [112], [122]. Important effects of altered cortisol levels on weight gain are also reported in Cushing׳s syndrome and Addison׳s disease, which are both associated with effects such as central obesity/hypercortisolism and weight loss/hypocortisolism, respectively [123].
HPA轴的失调与一些饮食失调有关[119]，[120]，主要是由于胰岛素，NPY水平和其他参与食物摄入调节的肽的变化，这些肽可以通过皮质醇代谢调节[112]。在健康男性中，通过给予糖皮质激素泼尼松刺激食物摄入[121]，而饮食影响皮质醇代谢，影响HPA轴和可口食物的奖励回路[112]，[122]。在库欣氏综合征和阿狄森氏病中也报告了皮质醇水平改变对体重增加的重要影响，这两种疾病分别与向心性肥胖/皮质醇增多和体重减轻/皮质醇减少等效应相关[123]。

5. Sleep, stress, and metabolism
5.睡眠、压力和新陈代谢 

Because of the new lifestyle imposed by work and family, physical and psychological problems, and social changes due to internet and television, stress and sleep restriction have become endemic, with a major impact on the metabolic process. Importantly, stress hormone levels correlate positively with decreased sleep duration, while both are associated with obesity, metabolic syndrome, and eating disorders [73]. A study by Galvao and colleagues [124] showed that rats subjected to 96 h of paradoxical sleep deprivation present increased immunoreactivity for CRH and orexin as well as higher levels of ACTH and corticosterone, in addition to increased diurnal food intake, but without changes in global food intake. A negative correlation was found between corticosterone and body weight gain throughout paradoxical sleep deprivation [124].
由于工作和家庭带来的新生活方式，身体和心理问题，以及互联网和电视带来的社会变化，压力和睡眠限制已经成为流行病，对新陈代谢过程产生重大影响。重要的是，应激激素水平与睡眠时间减少呈正相关，而两者都与肥胖，代谢综合征和饮食失调有关[73]。Galvao及其同事的一项研究[124]表明，接受96小时异相睡眠剥夺的大鼠表现出CRH和食欲素的免疫反应性增加，以及ACTH和皮质酮水平升高，此外还增加了日间食物摄入量，但总体食物摄入量没有变化。在异相睡眠剥夺过程中，发现皮质酮与体重增加呈负相关[124]。

Stress is known to reduce SWS, REM sleep, and delta power, as well as to affect metabolism in rodents, with the magnitude varying according to the type and duration of stress exposure [73]. Sleep deprivation, in turn, activates many stress-related pathways including the HPA axis and sympathetic nervous system, which indirectly modulate arousal and affect the metabolism [26], [125]. It has been proposed that the bidirectional relationship between sleep and stress and its impact on metabolism are, in part, mediated by hypocretin circuitry. Hypocretinergic cells project to several CRH-responsive regions in the central nervous system, including locus coeruleus, the PVN, the bed nucleus of the stria terminalis and the central amygdala [126].
已知压力会降低SWS、REM睡眠和δ功率，并影响啮齿动物的新陈代谢，其程度根据压力暴露的类型和持续时间而变化[73]。睡眠剥夺反过来会激活许多与压力相关的途径，包括HPA轴和交感神经系统，间接调节唤醒并影响新陈代谢[26]，[125]。有人提出，睡眠和压力之间的双向关系及其对新陈代谢的影响，部分是由下丘脑泌素回路介导的。下丘脑分泌素能细胞投射到中枢神经系统的几个CRH反应区域，包括蓝斑、PVN、终纹床核和中央杏仁核[126]。

Sleep deprivation per se is associated with HPA axis hyperactivity and negatively affects glucose tolerance [16]. The mechanism involved in impaired glucose metabolism following changes in the sleep–wake cycle seems to be the decreased efficacy of the negative feedback regulation of the HPA axis [42]. Activation of HPA axis may be a risk factor in the development of metabolic syndrome in OSA, via increased visceral obesity, insulin resistance, and sympathetic activity as well as changes in leptin levels [4], [127]. However, HPA axis hyperactivity must be only one among several factors that mediate metabolic syndrome in OSA. On the other hand, a recent study in healthy women with clinically diagnosed primary chronic insomnia has demonstrated a dysregulation of circadian cortisol secretion despite normal sleep architecture. Although the limitation of a small number of participants, the authors found that increased midnight cortisol levels were not associated with impaired metabolism of glucose and lipids [128].
睡眠剥夺本身与HPA轴过度活跃相关，并对葡萄糖耐量产生负面影响[16]。睡眠-觉醒周期变化后葡萄糖代谢受损的机制似乎是HPA轴负反馈调节的有效性降低[42]。HPA轴的激活可能是OSA中代谢综合征发展的风险因素，通过增加内脏肥胖、胰岛素抵抗和交感神经活动以及瘦素水平的变化[4]，[127]。然而，HPA轴过度活跃肯定只是介导阻塞性睡眠呼吸暂停综合征的几个因素之一。另一方面，最近一项对临床诊断为原发性慢性失眠的健康女性的研究表明，尽管睡眠结构正常，但昼夜皮质醇分泌失调。 尽管受少数参与者的限制，但作者发现午夜皮质醇水平升高与葡萄糖和脂质代谢受损无关[128]。

The bidirectional interaction between sleep and the HPA axis is complex. Current studies suggest that HPA hyperactivity, sleep loss, and sleep disturbances are closely linked in a vicious circle and play a role in the pathogenesis of metabolic disorders. Understanding sleep and stress system physiology is essential for elucidating the physiopathology of these syndromes and revealing new ways of prevention and treatment.
睡眠和HPA轴之间的双向相互作用是复杂的。目前的研究表明，下丘脑-垂体-肾上腺皮质功能亢进、睡眠不足和睡眠障碍在恶性循环中密切相关，并在代谢紊乱的发病机制中发挥作用。了解睡眠和压力系统生理学对于阐明这些综合征的生理病理学和揭示预防和治疗的新方法至关重要。

6. Summary and conclusions
6.总结和结论 

The current review provides evidence for overlap between sleep, stress, and metabolism, which can explain, at least in part, the outcomes observed in the modern society, where sleep deprivation, overnutrition, and chronic exposure to stress potentially lead to the increased incidence and prevalence of metabolic disorders such as obesity and type 2 diabetes. Through hyperactivation of the HPA axis and changes in the neuroendocrine response, sleep loss and chronic stress can lead to metabolic dysfunction. The HPA axis dysregulation is commonly seen in obesity, sleep deprivation, and sleep disorders such as OSA and insomnia. Conversely, sleep architecture and metabolism are impaired in hypercortisolism conditions such as Cushing׳s disease, confirming the close relationship between sleep, stress and metabolism, which is summarized in Fig. 2. We conclude that good sleep quality achieved through sleep hygiene and treatment of sleep disorders, in addition to nutritional education with regular meal frequency and circadian alignment of food intake, would be interesting strategies for preventing metabolic disorders. Targeting 11β-HSD1, a key enzyme in cortisol metabolism in peripheral tissues, and the hypocretin system, which actively and partially regulates the interconnection between sleep, stress and metabolism, might represent a promising therapeutic option for obesity, insulin resistance, and other consequences of excess glucocorticoids which arise from interactions between sleep and stress.
目前的综述提供了睡眠，压力和代谢之间重叠的证据，这至少可以部分解释现代社会中观察到的结果，其中睡眠剥夺，营养过剩和长期暴露于压力可能导致肥胖和2型糖尿病等代谢紊乱的发病率和患病率增加。通过HPA轴的过度激活和神经内分泌反应的变化，睡眠不足和慢性应激可导致代谢功能障碍。HPA轴失调常见于肥胖、睡眠剥夺和睡眠障碍如OSA和失眠。相反，皮质醇增多症（如库欣氏病）的睡眠结构和代谢受损，证实了睡眠、压力和代谢之间的密切关系，如图2所示。 我们的结论是，良好的睡眠质量，通过睡眠卫生和治疗睡眠障碍，除了营养教育与定期进餐频率和昼夜调整的食物摄入量，将是有趣的战略，以防止代谢紊乱。靶向11β-HSD 1（外周组织中皮质醇代谢的关键酶）和下丘脑泌素系统（其主动和部分调节睡眠、压力和代谢之间的相互联系）可能代表了治疗肥胖、胰岛素抵抗和由睡眠和压力之间的相互作用引起的过量糖皮质激素的其他后果的有希望的治疗选择。

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Fig. 2  图2

Schematic of the main interactions between sleep, stress and metabolism. Sleep disorders which can lead to sleep loss share common pathways with stress system via HPA axis activation on the metabolic dysfunction, contributing to increased risk of developing obesity and diabetes.
睡眠、压力和新陈代谢之间主要相互作用的示意图。睡眠障碍可导致睡眠不足，与应激系统通过HPA轴激活代谢功能障碍共享共同的途径，导致肥胖和糖尿病的风险增加。

Review criteria 审查标准

A search for original and review articles that focus on sleep, stress, and metabolism was performed in PubMed. The search terms used were “sleep”, “sleep disorders”, “sleep loss”, “sleep deprivation”, “stress”, “HPA axis”, “cortisol”, “corticosterone”, “metabolism”, “diabetes”, “obesity”, “glucose”, “insulin”, “metabolic”, “endocrine”. We also searched the reference lists of identified articles for further papers. Articles were restricted to human studies. In order to limit the number of references, we selected, whenever possible, a recent review complemented by original papers published after the review.
在PubMed中检索了关注睡眠、压力和代谢的原始和综述文章。使用的检索词为“睡眠”、“睡眠障碍”、“睡眠丧失”、“睡眠剥夺”、“压力”、“HPA轴”、“皮质醇”、“皮质酮”、“代谢”、“糖尿病”、“肥胖”、“葡萄糖”、“胰岛素”、“代谢”、“内分泌”。我们还检索了已识别文章的参考文献列表，以获取更多论文。文章仅限于人体研究。为了限制参考文献的数量，我们尽可能地选择了最近发表的综述，并在综述后发表了原始论文。

Acknowledgments 致谢

References