Regulation of appetite is dependent on crosstalk between the gut and the brain, which is a pathway described as the gut-brain axis (GBA). Three primary appetite-regulating hormones that are secreted in the gut as a response to eating a meal are glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), and peptide YY (PYY). When these hormones are secreted, the GBA responds to reduce appetite. However, secretion of these hormones and the response of the GBA can vary depending on the types of nutrients consumed. This narrative review describes how the gut secretes GLP-1, CCK, and PYY in response to proteins, carbohydrates, and fats. In addition, the GBA response based on the quality of the meal is described in the context of which meal types produce greater appetite suppression. Last, the beneficiary role of exercise as a mediator of appetite regulation is highlighted.
Keywords: Diet, Vagus nerve, Nucleus tractus solitarius, Energy intake, Weight loss, Education
Blunted appetite regulation is a hallmark of an advanced obesogenic state that hinders weight loss harder. The link between food intake and the drive to eat is the gut-brain axis (GBA), where appetite is regulated. The GBA is interconnected in the medulla of the brainstem, where the nucleus tractus solitarius (NTS) receives the vagus nerve (VN) afferent fibers input originating from the gut. For context, the gut is comprised of the stomach, small intestine, and large intestine. Distension and secretion of hormones elicited by food intake in the gut cause a signal that is received by the afferent branch of the VN. This signal is transmitted by the VN to the NTS, where subsequent upper brain regions (superior to the brainstem) are stimulated to suppress appetite and induce meal termination. A representation of GBA signaling to the brain is presented.
In contrast, during a fasted state, the GBA can stimulate the VN to increase the desire to eat. Although the GBA is tightly regulated, there is evidence suggesting that people with obesity have a dysregulated GBA that predisposes them to greater food cravings and increased food intake due to a lack of appetite regulation. For optimal appetite regulation, fully functional neurotransmitter activity is required. For example, dopamine can promote cravings that lead to eating, while it is also required to induce the feeling of “reward” that is required to suppress appetite. Because dopamine has a potent role in regulating eating behavior, downregulation of its prefrontal cortex receptors that is driven by overstimulation of reward-like behaviors is a major factor of a dysregulated GBA. In the context of food intake, stimulation of the GBA and subsequent NTS signal and dopamine release differ based on the type of nutrient consumed. Because the GBA has many interrelated mechanisms to correctly regulate appetite, the scope of this narrative review is to describe the connection between the GBA and nutrient intake while elaborating how nutrient type can affect appetite regulation.
We briefly described modulation of appetite controlled by the GBA. However, appetite and hunger are not the same. Appetite refers to the cephalic (upper brain regions) regulation of eating, whereas hunger is a process or physiological drive that aims to initiate eating and is signaled by an array of physiological stimuli, such as the “growling and emptiness of the stomach”, a decrease in blood glucose, and an increase in ghrelin concentration. Based on these definitions, appetite can be experienced at any point, whereas hunger is experienced only under fasted conditions. Herein, throughout this review, we will only describe GBA responses as they relate to appetite (drive to eat).
A common weight loss approach is to follow a hypocaloric diet that restricts overall nutrient intake. From an energy balance point of view, such an approach is logical and practical because consuming fewer calories than what is expended daily should lead to weight loss over time. However, this paradigm regularly contradicts itself, because a hypocaloric diet can lead to a reduction in energy expenditure. This concept is referred as the metabolic set point, where the body reduces the nonessential energetic demands to prevent energy deficiency and meet metabolic demands. Therefore, maintaining the weight loss achieved via a hypocaloric diet can be difficult. The challenges to sustaining a hypocaloric diet to achieve weight loss are related to the physiological abilities of our body to respond to energy intake. In essence, regardless of meal size, the GBA is not capable of sensing or determining caloric intake at a given meal. In contrast, meal content (macro and micronutrients) is the primary mediator of GBA stimulation. For example, a sugar-based snack might have the same caloric content as a protein-based snack. However, the protein-based snack will produce greater satiety signaling and reduce food intake in comparison to the sugar-based snack. That is why the nutrient content rather than the caloric intake, in combination with the stretching of gastrointestinal walls, determines the ability of the cells in the gut to secrete appetite-regulating hormones. Herein, a dysregulated GBA that cannot adequately sense the hormonal secretions from the gut will have a blunted capability to regulate appetite and can be associated with hedonic eating and promote an obesogenic state.
High consumption of protein or amino acids is a good method to reduce total energy intake by increasing satiety in comparison to that gained from carbohydrates and fats. Based on this, it is expected that the GBA can effectively sense the intake of protein and inhibit appetite accordingly. Specifically, when protein is consumed, enteroendocrine cells located in the small intestine secrete cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY). These three are defined as anorexigenic (appetite suppressant) hormones. When CCK is released, the nearby region of the small intestine that holds the VN afferents receives the signal from CCK when it binds to its CCK type 1 receptors (CCK 1). When CCK binds to CCK1, the GBA mediates the passage of a satiety signal from the gut to the brain and suppresses appetite to help reduce food intake. Similarly, GLP-1 and PYY have the same effect of binding to their receptor located in VN afferents and producing an anorexigenic signal.
Although the overall effect of protein intake is an anorexigenic response, the composition of the protein molecules is important. For example, the satiating effects of protein intake can be further increased by consuming proteins that contain specific amino acids like arginine, lysine, and glutamic acid. Compared to other amino acids, these have shown a greater ability to produce an anorexigenic response. This is an important consideration because it exemplifies how not only macronutrient type, but also quality in terms of composition are important. Leucine is an amino acid often thought to be a major precursor of an anorexigenic response. However, it is speculated that leucine acts differently than other amino acids, which produce an anorexigenic response by stimulating the GBA. In contrast, leucine stimulates protein synthesis and growth that are only possible if there is sufficient energy available. Therefore, it indirectly inhibits appetite by signaling that there are enough nutrients to synthesize proteins but does not react to nutrient type. More research is warranted to better understand how specific amino acids affect appetite regulation.
In contrast to protein intake, carbohydrates have a lower capability to stimulate the secretion of CCK. Furthermore, a carbohydrate-rich meal has a lower duration in its satiety-inducing effect compared to a protein-based meal. In part, the difference is attributed to gastric emptying, where carbohydrates can be digested faster than proteins. Therefore, from a satiety point of view, CCK will signal the GBA for longer and promote a longer satiety response when consuming protein rather than carbohydrates. Furthermore, a carbohydrate-rich meal elicits lower secretion of both GLP-1 and PYY and a sh
