There is growing evidence that reduced sleep duration in children is associated with an increased risk of being overweight and obese later in life. A meta-analysis confirmed a significant association between short sleep duration and adverse changes in body mass index (BMI) in infants, children, and adolescents ^[1][2][3][35,36,37], and quantified the associated risk of a greater risk of overweight/obesity in children with short sleep durations. The findings further support the existence of a positive association between reduced nighttime sleep duration and childhood obesity. Additionally, the results of interventions targeting sleep suggest that improved sleep duration or quality may be beneficial in reducing weight gain in children ^[4][38]. Notably, the results of the experiments in healthy adult volunteers found that food intake increased during sleep deprivation, providing the energy needed for additional wakefulness ^[5][6][39,40]. Conversely, switching from sleep deprivation to adequate/restorative sleep reduced energy intake, especially fat and carbohydrate components, and led to weight loss ^[7][41], indicating that sleep regulates body weight by influencing the balance between energy expenditure and intake and that exploring this balance would facilitate further interventions for childhood obesity. Interestingly, current research suggests that reduced sleep duration can affect a child’s ability to self-regulate his/her appetite and develop poor eating patterns, thereby increasing the risk of overeating ^[8][9][42,43]. Hjorth et al. ^[10][44] also demonstrated that a 1 h decrease in sleep duration increased the intake of added sugar and sugar-sweetened beverages. These indicate that investigating the effects of sleep deprivation on the appetite regulation of children would be useful for further elucidating the mechanisms underlying weight gain in children induced by sleep deprivation.

In mammals, the melanocortin system is a key neuroendocrine network that plays a critical role in the regulation of appetite and energy homeostasis. The hypothalamic “melanocortin” neural loop is involved in the regulation of energy homeostasis. This loop is composed of appetite-suppressing POMC neurons in the hypothalamic arcuate nucleus, appetite-promoting AgRP neurons, melanocortin receptor-4 (MC4R)-positive neurons in the paraventricular nucleus, and the neural projections between them ^[12][46]. During satiety, POMC neurons project and release α-MSH, which activates MC4R on paraventricular nucleus neurons to reduce appetite, while during starvation, AgRP neurons send inhibitory GABAergic neural projections to suppress POMC neuronal excitability and can also secrete AgRP to antagonize the activation of MC4R by POMC, thus enhancing appetite. Thus, AgRP neurons, POMC neurons, and paraventricular nucleus neurons form an important neural loop to maintain the energy balance of the body ^[13][47].

Orexin was first discovered in 1998 in rat brain tissue extracts and is synthesized in the lateral hypothalamic region ^[14][48]. Orexin neurons are involved in the control of various homeostatic functions, including feeding and energy expenditure ^[15][49]. When injected intraperitoneally, orexin stimulates food intake ^[16][50]. Fasting then leads to an upregulation of orexin mRNA levels ^[17][51] and increases the number of excitatory synapses on orexin neurons ^[18][52]. Blocking orexin receptors reduces food intake ^[19][53] and binge-eating behavior ^[20][54].

Ghrelin release from neurons in the gastric oxyntic gland and the arcuate nucleus of the hypothalamus (ARC) stimulates growth hormone release and food intake ^[21][55] and can increase synaptic activity in NPY/AgRP neurons. This effect is achieved by activating an adenylate-activated protein kinase (AMP-activated protein kinase, AMPK)-dependent positive feedback loop, and the effects of ghrelin persist for several hours even after the removal of this kinase ^[22][56]. In addition, intravenous administration of ghrelin may also promote appetite and increase food intake. A study conducted on healthy volunteers showed that food intake was significantly increased in the intravenous hunger hormone group. The appetite-enhancing effect of ghrelin was associated with increased expression of AgRP mRNA and decreased expression of POMC mRNA.

Leptin is mostly derived from white adipose tissue and has a wide range of biological effects. Its main role is to suppress appetite in the hypothalamus, increase energy expenditure and inhibit fat synthesis. Abnormal adipose tissue function in leptin-deficient mice, secondary to overeating and reduced energy expenditure, leads to obesity. Leptin receptors are widely present in the hypothalamus, hippocampus, and other central nervous systems and peripheral organs ^[23][57]. Depending on the site of binding of nonreceptor type tyrosine kinase 2 (Janus kinase 2, JAK2) to the leptin receptor protein, its signaling pathway can be divided into the JAK2/signal transducers and activators of transcription 3 (STAT3) pathway, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, and insulin receptor substrate (IRS)/phosphatidylinositol-3-kinase (PI3K) pathway ^[24][58].

Insulin was first discovered 100 years ago by Banting and Best in extracts from the dog pancreas. Insulin is considered to be a peripheral regulator of blood glucose levels and is used to treat type 1 and type 2 diabetes in more than 450 million people worldwide ^[25][59]. Elevated blood glucose levels stimulate the release of insulin, which is circulated in the bloodstream and binds to insulin receptors on the cell membranes of tissues, such as the liver, muscle, and fat. In addition, despite early assertions that the central nervous system is insensitive to insulin, it has recently been discovered that insulin is also synthesized and secreted by nerve cells in the brain. Cortical glial cells may be one of the sources of insulin in the brain ^[26][60], and insulin levels in the brain are much higher than plasma insulin levels. Peripheral insulin can also be transferred to the brain via the blood–brain barrier. In the hypothalamus, insulin is involved in the regulation of glucose homeostasis, central glucose transport, appetite, and metabolism ^[27][61]. Classic central insulin signaling pathways include the hypothalamic IR/IRS/PI3K/AKT/STAT3 pathway and the IR/IRS/PI3K/ATP pathway.

Glutamate transporter-1 (GLT1) is an astrocytic transporter protein that is responsible for glutamatergic transmission in the brain. Sleep deprivation significantly alters the localization of glutamate transporter-1 and the excitability of orexin neurons ^[28][63]. Specifically, after sleep deprivation, GLT1 was found to be reduced around the cytosol of orexin neurons, leading to different forms of synaptic plasticity ^[28][63]. Another rat model also demonstrated that sleep deprivation increased the expression of orexin and that increased expression of orexin was able to inhibit signaling in the ERK1/2 pathway ^[29][64]. Although the mechanisms by which sleep deprivation regulates appetite and hunger hormone expression are currently unknown, available studies also suggest that it may affect appetite by influencing appetite neuronal excitability as well as hunger hormone levels ^[30][65].

In one research study on sleep deprivation in rats, the mRNA levels of leptin receptor (LepRb) in the prefrontal cortex were found to be decreased as compared to the control group by PCR, while the mRNA levels of leptin receptors in the hypothalamus were significantly increased ^[31][66]. Furthermore, a study by a team elucidated the biological regulation of leptin receptors in a rat model through the JAK2/STAT3 signaling pathway ^[32][26]. Additionally, another study investigating the treatment of appetite suppression with amphetamine (AMPH) found that LepRb/JAK2/STAT3 signaling in the hypothalamus was involved in the regulation of appetite by AMPH ^[33][67]. These results showed that sleep deprivation may act as a regulator of appetite-controlling by inducing leptin receptor expression and compromising the JAK2/STAT3 signaling pathway. However, current studies lack in vivo and ex vivo experiments to directly confirm the existence of such mechanisms. Notably, a growing number of studies suggest that circadian rhythms can control energy metabolism ^[34][68]. The circadian rhythm, also known as the biological clock, is prevalent in the biological world and is a physiological phenomenon with an approximately 24-h cycle. The circadian system organizes metabolism, physiology, and behavior in a daily circadian cycle that includes a central pacemaker in the brain and a series of clocks in peripheral tissues throughout the body, including the liver, muscle, and adipose tissues ^{[35][36][37][38]}[69,70,71,72]. Epidemiological studies have shown that sleep deprivation, shift work, and jet lag syndrome can all cause circadian clock disruption ^[39][40][73,74]. A in vivo experiment found that sleep deprivation reduced the expression of circadian clock genes in the hypothalamus of rats ^[32][26]. Can sleep deprivation affect hypothalamic feeding by modulating changes in circadian rhythms? The results of Kettner et al. also showed that circadian rhythms enhanced the LepRb response to serum leptin within the ARC, conversely, chronic circadian rhythm disturbances led to LepRb desensitization to circulating leptin, resulting in leptin resistance ^[41][75]. Together, the above studies suggest that sleep deprivation may regulate appetite by inducing disturbances in biological rhythms to decrease the sensitivity of LepRb to circulating leptin.

Animal studies have similarly demonstrated that sleep deprivation leads to a reduction of insulin sensitivity through a rhesus monkey model ^[42][76]. In another model of paradoxical sleep deprivation (PSD) based on Wistar rats, researchers found an upregulation in food intake and a concomitant decrease in insulin levels during the light phase ^[43][77]. Eight Drosophila insulin-like peptides (DILPs) have been identified in Drosophila, and are involved in the regulation of carbohydrate concentrations in the hemolymph and the accumulation of storage metabolites. It was found that insulin-like peptides are able to regulate appetite in Drosophila ^[44][78]. Remarkably, this regulatory mechanism also exists in mammals. A study conducted by Chruvattil et al. ^[45][79] in Charles Foster rats showed that insulin signaling in the hypothalamus was involved in regulating the feeding behavior of rats, and further studies also found that insulin could regulate appetite in rats by regulating the expression of SIRT1 and activating the AMPK signaling pathway.

Currently, investigations on children and adolescents have shown that sleep deprivation affects serum leptin levels, influencing appetite regulation and leading to weight gain ^[46][80]. In a randomized crossover experiment of 19 healthy men under normal sleep and sleep deprivation conditions, researchers took blood samples from volunteers during standardized caloric feeding and found that ghrelin levels increased after sleep deprivation, which may be a source of it ^[47][81]. However, there are also studies showing that sleep deprivation is not associated with changes in orexin and ghrelin ^[48][82]. These inconsistent results may result from differences in the duration of sleep deprivation, differences in eating conditions during hormone measurements (e.g., standardized versus arbitrary ingestion), or differences in the timing and frequency of blood sampling. The effects of sleep restriction on appetite-regulating hormones may not be detected when measurements are taken during uncontrolled caloric intake.

In a randomized controlled trial, 10 healthy individuals underwent 4 nights of normal sleep (8 h of bed rest) and 4 nights of sleep deprivation (4 h of bed rest) in a sleep laboratory. Insulin measurements were performed early each morning, and the results showed that the area under the insulin curve was higher in the sleep deprivation experiment than in the control group ^[49][83]. Additionally, a narrative review based on clinical evidence reported that sleep deprivation or poor sleep quality was associated with reduced insulin sensitivity ^[50][84]. The incretin hormone, glucagon-like peptide 1 (GLP-1) induces satiety and increases postprandial insulin secretion. A study on one-night sleep deprivation in healthy men showed no significant effects on circulating concentrations of total serum GLP-1 but induced temporal changes in the peak GLP-1 response to breakfast intake ^[51][85]. The changes in postprandial GLP-1 signaling contribute to the impairment of sleep loss on glucose homeostasis and food intake control, which should be focused on in future studies.