Numerous animal and clinical studies have demonstrated that the arcuate nucleus of the hypothalamus, a central regulator of appetite, plays a significant role in modulating feeding behavior. However, current research primarily focuses on long-term dietary changes and their effects on the body, with limited investigation into neuroendocrine dynamics during individual meals across diverse populations. In contrast to long-term dietary adjustments, directives for dietary behavior during a specific meal are more actionable, potentially enhancing patient adherence and achieving better outcomes in dietary behavior interventions. This review aimed to explore the neural pathways and endocrine changes activated by gastrointestinal expansion and variations in blood nutrient levels during a single meal, with the goal of informing dietary behavior guidance.
The driving forces of eating can be attributed to two distinct factors: (1) the sensation of hunger caused by gastrointestinal peristalsis and (2) signals from the brain that generate the desire to eat. The hypothalamic arcuate nucleus (ARC), located adjacent to the third ventricle, is widely recognized as a central regulator of appetite. This region features a specialized and more permeable blood–brain barrier compared to other brain regions. The increased permeability allows circulating nutrients and hormones—such as glucose, leptin, and insulin—to directly access agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons within the ARC. This direct access makes these neurons highly responsive to nutrient fluctuations, facilitating the regulation of energy homeostasis. Various appetite-regulating hormones including insulin, leptin, and peptide YY (PYY), as well as small-molecule nutrients such as amino acids and glucose, can directly stimulate these neurons and play a crucial role in appetite regulation.
Eating habits have been shown to affect energy metabolism and contribute to the development of metabolic diseases. Specifically, faster eating, higher cooking temperatures, fewer chews, and late eating have been associated with increased food intake and increased risk of obesity, diabetes, and hypertension. A high-fat diet (HFD) can remodel brain neurons, alter the dominant species of intestinal flora, increase body fat deposition, and contribute to metabolic disorders. Conversely, intermittent fasting improves insulin sensitivity, reduces blood triglyceride and cholesterol levels, alleviates chronic inflammation, and helps regulate metabolic disorders.
To date, few studies have focused on the effects of feeding during a specific meal or conducted a comprehensive analysis of neurological and humoral changes. Compared to existing dietary guidelines, behavior guidance for a single meal is more specific and practical, aiding patients in self-control and implementation. In this review, we explore the factors that influence appetite, focusing on the feeding process during a complete eating cycle. We analyze the immediate neurological and humoral changes observed in animals. Due to limitations in current research, this article predominantly focuses on experimental mice, while findings from mouse studies may offer insights applicable to human research. We also discuss how these changes impact appetite during this process. This review provides insights for dietary behavior guidance.
For a relatively balanced meal in terms of both quantity and quality, gastric emptying in humans typically takes 4–6 h. Feelings of hunger typically emerge around this time, marking the starting point of the feeding process addressed in this review. The orexigenic effect of AgRP depends on the release of neuropeptide Y (NPY) and gamma-aminobutyric acid (GABA). Mouse experiments have demonstrated that mice deficient in NPY or GABA transporters do not rapidly increase food intake when AgRP neurons are activated. This finding indicates that NPY and GABA mediate the rapid, short-term effects of AgRP on feeding behavior. In contrast, the orexigenic effect induced by AgRP itself is slower and more prolonged. In addition to stimulating appetite, activating AgRP decreases energy expenditure, enhances carbohydrate utilization, and reduces fat breakdown. Under conditions of extreme hunger, the AgRP→parabrachial nucleus (PBN) pathway suppresses pain responses, allowing animals to prioritize foraging for food. Mouse experiments have demonstrated that activating AgRP/NPY neurons increases their willingness to take greater risks when seeking food.
Upon food discovery, visual and olfactory signals transmitted into the brain activate different brain areas; AgRP secretion rapidly decreases, while POMC neurons, which antagonize AgRP, are rapidly activated. Simultaneously, saliva, digestive enzymes, insulin, and other substances are secreted to prepare food intake. Vagal receptors in the oropharyngeal area detect changes in taste and tension, activating the vagus nerve to initiate the vagovagal reflex of the stomach and facilitate the smooth entry of food into the stomach. Vagal receptors distributed throughout the gastrointestinal tract sense changes in tension and nutrient levels within the digestive system. These stimuli are transmitted to the brain, inducing satiety and activating secretory cells in the intestine to release appetite-suppressing hormones, such as PYY and serotonin, which stimulate the hypothalamus to create a feeling of fullness. Through the coordinated actions of multiple factors, the eating event concludes as food is gradually digested into chyme in the stomach. As nutrients are absorbed by intestinal epithelial cells, blood glucose levels rise, providing the energy required for growth and activity. Over time, these nutrients—primarily glucose—are utilized, leading to decline in blood glucose levels, reduction in insulin secretion, and gradual increase in AgRP/NPY neuron activity, eventually triggering the next sensation of hunger. The trend of changes in the main neurohumoral regulation during eating is illustrated in Figure 1.
During the period between detection of food signals and swallowing, the body undergoes a series of anticipatory responses, collectively referred to as cephalic phase responses. These responses include the secretion of saliva, digestive enzymes, and insulin; they ensure rapid digestion, efficient food absorption, and effective nutrient metabolism. Recently, cephalic phase responses have gained increasing attention. Studies on rodents and humans have shown that, when transmitted to corresponding areas of the cerebral cortex, sensory food stimuli, such as visual, taste, and olfactory cues, have corresponding effects on subsequent eating behavior through different pathways, some of which are associated with the reward system.
The nucleus tractus solitarius (NTS) integrates these signals and relays them to the dorsal motor nucleus of the vagus nerve (DMV), initiating vagal nerve activity and mediating the early secretion of insulin. Although this hypothesis remains unconfirmed, it is well established that cephalic phase insulin release positively correlates with the amount of food ingested during a meal. The cephalic phase insulin release also counteracts hepatic glucose production mediated by glucagon, helping to maintain relatively stable blood glucose levels.
POMC neurons also influence the liver’s regulation of early-phase blood glucose after a meal. Upon sensing food cues, POMC neurons are rapidly activated and regulate the sympathetic nervous system of the liver in an mTOR-dependent manner, thereby controlling hepatic glycogenolysis. Additionally, AgRP neurons are rapidly and uniformly inhibited when detecting food cues, with the level of inhibition positively correlated with palatability and expected energy content of the food. This inhibitory response is mediated by GABAergic neurons expressing leptin receptors in the dorsomedial hypothalamus (DMH), and its duration is proportional to energy expenditure.
Although both types of neurons respond rapidly to food cues, they do not directly mediate the initiation or termination of eating behaviors. The dorsal vagal complex, located in the brainstem, receives input signals from the hypothalamus and integrates them with signals from the gastrointestinal tract via the vagus nerve, playing a key role in mediating eating behavior.
Food enters the stomach after chewing and swallowing, mixes with gastric juice, breaks down into chyme and then passes into the intestine for absorption. This process involves complex neurohumoral changes, primarily mediated by the sensory branches of the vagus nerve distributed throughout the stomach and intestinal walls. These changes stimulate vagal receptors in the oropharyngeal region, which transmit feeding signals to the stomach via the vagovagal reflex, initiating gastric accommodation. Gastric accommodation maintains the relative stability of intragastric pressure (IGP), a factor significantly correlated with satiety. A brief decrease in IGP is observed at the onset of eating. As food accumulates in the stomach, the muscles of the gastric cardia, fundus, and body gradually become tense, increasing IGP. The tension receptors widely distributed in the gastric walls are stimulated, transmitting signals via the nodose ganglion (NG) to the NTS, which mediates the sensation of fullness. The rate of gastric emptying during eating is higher than usual, allowing some incompletely digested chyme to enter the intestine, where it stimulates tension and chemoreceptors in the duodenal wall. Additionally, tension receptors in the gastrointestinal wall may be involved in regulating insulin secretion during eating.
Several gastrointestinal hormones, including ghrelin, glucagon-like peptide-1 (GLP-1), PYY, serotonin, and cholecystokinin (CCK), are involved in appetite regulation. Ghrelin, secreted by P/D1 cells in the gastric fundus, increases during fasting and rapidly decreases after eating, promoting feeding by sti
