Dietary strategies for appetite regulation: satiety and obesity management

Abstract

Increased prevalence of diseases associated with obesity has driven research into appetite suppression to reduce high-calorie intake. Dietary modulation of appetite is recognized as one of the most significant and effective ways to reduce the risk of obesity-related diseases. This review evaluates the roles of dietary nutrients and their metabolites in satiety and proposes dietary strategies for appetite regulation. Brain circuits of hunger, hormones and organs that directly control the appetite, and the role of gut microbiota in indirect appetite modulation are discussed in detail. We explored the impact of dietary nutrients and their metabolites on appetite, based on the basic mechanics of hunger. Additionally, based on the impact of different dietary factors on satiety, we outlined three strategies for appetite regulation: systems for controlled nutrient delivery to decelerate digestion, alteration of dietary physicochemical characteristics, and establishment of dietary rhythms. This review presents a theoretical framework for examining the influence of dietary nutrition on appetite regulation.

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1. Introduction

Overweight and obesity are significant risk factors for non-communicable diseases and have escalated into global concerns with their prevalence increasing dramatically.¹ In 2022, approximately 43% of adults globally were classified as overweight, while 16% were deemed obese, a figure that had more than doubled since 1990.² The health consequences linked to obesity and overweight are substantial, resulting in about 2.8 million fatalities each year and 35.8 million disability-adjusted life years. Moreover, they are serious risk factors for several non-communicable diseases, including hypertension, diabetes, stroke, and other chronic conditions.² Individuals with obesity encounter societal stigma and discrimination, leading to mental health issues that prompt them to seek pharmaceutical and surgical weight loss treatments.³ Nevertheless, the negative consequences of pharmaceutical and surgical weight loss methods have caused some consumers to be reluctant to use them, and accordingly, the appeal of nutritional approaches that diminish appetite and improve fullness has augmented.

Appetite, in the absolute sense, is described as the desire to feed. The hunger appetite neural pathways are activated or inhibited by key nutrients, water and sodium.⁴ Hunger and appetite regulate host's energy balance, satiety (the feeling of fullness that persists after eating), and food intake behavior and are closely related to body fat accumulation and obesity.^5,6 Obesity induced by overeating is a burden on overall health. Compared with that in thin people, the response to the nutrient infusion is significantly reduced in the obese, and the response to peptide YY (PYY), pancreatic polypeptide, glucose inhibitory peptide, and glucagon-like peptide-1 (GLP-1) is significantly delayed.⁷ The combined intake of fat and sugar is the main factor contributing to hyperphagia, and it contributes to the development of obesity. A high-fat diet, even for a short term, activates prepronociceptin (PNOC)-expressing neurons (PNOC^ARC) in the arcuate nucleus of the hypothalamus (ARC), which is an area that contains multiple neurons involved in maintaining energy balance, causing overeating.⁸ A high-sugar or high-fat food intake triggers the taste neurons to desire more, improves pleasure and stimulates the intake of sugar and fat.^9,10 Both high-sugar and high-fat diets reversibly dampen the rapid agouti-related protein (AgRP) neuron inhibition following food presentation and promote the intake of more food, exacerbating obesity.¹¹ Conversely, obesity leads to increased food desire. In obese individuals, visceral fat accumulates under the influence of external nutrients. Adipocyte O-linked beta-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) stimulates hyperphagia by the transcriptional activation of de-novo lipid desaturation and the accumulation of N-arachidonyl ethanolamine (an endogenous appetite-inducing cannabinoid).¹² Meanwhile, adipose OGT overexpression inhibits lipolysis and exacerbates diet-induced obesity.¹³ High-fat diets can rapidly upregulate the gene expression of uncoupling protein 2 (Ucp2) in the microglia and alter mitochondrial function and morphology, while specific Ucp2 knockouts in microglia reduce feeding and resist obesity via changes in synaptic input organization and activation of the POMC neurons and astrogliosis.¹⁴ Thus, reasonable management of hunger (appetite) is important for obesity regulation.

At present, various appetite-influencing factors controlling food intake, such as emotion, age, exercise, genes, environment, and nutrients, are investigated.^15–17 Undoubtedly, dietary intervention is the direct way to achieve satiety. Notably, gut microbiota and metabolites of nutrients, such as γ-aminobutyric acid (GABA), bile acids (BAs), and short-chain fatty acids (SCFAs), also participate in the neural regulation of appetite and host metabolism.¹⁸ This review examines the categorization of appetite and its related neuroregulatory pathways, emphasizing the direct influence of prevalent food components on hunger appetite signals and the indirect augmentation of host satiety via compounds generated by the intestinal flora. The functions of gut-secreted factors, such as GLP-1, cholecystokinin (CCK), and PYY, with respect to macronutrient (proteins, carbohydrates, and fats) metabolism are examined. Additionally, the impact of AgRP neurons and associated hypothalamic circuits on appetite regulation is examined. Dietary options designed based on these pathways to enhance appetite regulation are presented, serving as a comprehensive reference for obese patients.

2. Appetite types and related neural pathways

Daily intake of adequate amounts of various nutrients is essential to maintain the stability of the internal environment in the body. Nutritional imbalance is associated with a variety of diseases. For example, a high-sodium diet increases the risk of cognitive and cardiovascular diseases,^19,20 water homeostasis disorders induce osmolality-related diseases,^21,22 and overfeeding leads to obesity.²³ Therefore, optimizing and managing the intake of nutrients is essential for optimal health. Thirst, sodium appetite, and hunger are the main categories related to managing food intake.⁴ The neural circuits of thirst and sodium appetite act rapidly, and their neural activities can quickly drive and terminate the water and sodium intake behavior,^24,25 while the hunger circuit acts more slowly and takes longer to respond to feeding behavior (Fig. 1).^26,27 The sensory regulation of appetite circuits relevant to different nutrients (dietary energy, water, and sodium) is governed by other body parts.^28,29 These regulatory signals, including chemosensory, hormonal, and gut-brain afferent pathways, play a key role in appetite induction and satiety.

Fig. 1 Relationship between different appetite activation signals and response stimulation time.

2.1 Neuroregulation of thirst

Thirst, sodium appetite, and hunger circuits receive pre-absorption feed-forward satiety signals through multiple sensory systems after nutrient intake. Different internal receptor neurons in the lamina terminalis (LT), solitary-related nucleus, and hypothalamic arcuate nucleus in brain structure regulate thirst, sodium appetite and hunger, respectively.⁴ The subfornical organ (SFO) and organum vasculosum lamina terminalis (OVLT), situated beyond the blood–brain barrier, are capable of monitoring blood osmotic pressure and detecting various hormonal signals, thereby regulating fluid homeostasis.³⁰ In contrast, the median preoptic nucleus (MnPO) synthesizes information to modulate vasopressin secretion through excitatory neurons that express nitric oxide synthase.³¹ These three together constitute the LT in the forebrain, stimulating or inhibiting thirst in humans.³² Additionally, the thirst neurons in LT can be rapidly suppressed by liquid gulping signals and gastrointestinal osmolality information.^33,34 Therefore, the gut hypotonic responses mediated in vivo by intestinal water injection stimulate the vagal afferents innervating the hepatic portal area (HPA) and regulate thirst and drinking behavior in a very short time.^35,36

2.2 Neuroregulation of sodium appetite

Specific neurons in the nucleus of the solitary tract (NTS) respond to internal sodium depletion through aldosterone and angiotensin.^37,38 The stimulation signal is transmitted to the downstream brain region where the pre-locus coeruleus (pre-LC) is located, driving salt intake behavior.³⁹ Meanwhile, increased plasma secretin levels caused by sodium deficiency enter the brain to activate secretin-responsive neurons in NTS, further activating the paraventricular nucleus (PVN) of the hypothalamus and promoting sodium uptake.⁴⁰ Moreover, sodium depletion activates neurons in the sensory regions of the forebrain LT.^41,42 The activation of SFO-prostaglandin E2 and its receptor (Ptger3) neurons could increase the intake of even an aversively high-concentration salt solution.³⁹

2.3 Neuroregulation of hunger

Animal feeding behavior can be categorized into (1) homeostatic feeding, which is the consumption of food required to sustain normal weight and metabolic function, and (2) hedonic feeding, which is food intake motivated by sensory perception or pleasure.^43,44 Hedonic feeding arises from reward and cognitive functions, involves orexins and interactions among dopaminergic, opioidergic and glutamatergic signaling, and can potentially override homeostasis regulation.^45,46 Some of the nuclei in the basal part of the hypothalamus are considered key in regulating dietary energy balance and hunger signals.⁴⁷ ARC and the lateral hypothalamic area (LHA) are the regions associated with appetite signal synthesis and release; PVN is the region of appetite signal interaction, while the suprachiasmatic nucleus (SCN), ventromedial nucleus (VMN), and dorsomedial nucleus (DMN) are regions involved in hunger regulation.⁴⁸ The neurons that co-express agouti-related peptide and neuropeptide-Y (AgRP/NPY) signal hunger and stimulate food intake, while anorexic pro-opiomelanocortin/cocaine-and amphetamine-related transcript (POMC/CART) neurons signal satiety and reduce food intake (Fig. 2).⁴⁹ These neural circuits controlling hunger and appetite are modulated by gastrointestinal hormones, including GLP-1, CCK, PYY, and oxyntomodulin (OXM). These hormones exert their effects through the vagus nerve pathway or other hormones released by associated organs, such as the stomach, pancreas, and adipose tissue, which activate specific receptors. The neuronal activity of AgRP is responsive, and its base levels decline rapidly when feeding begins.⁵⁰ By interacting with melanocortin 4 receptors (MC4R), AgRP can delay chronic feeding response.^51,52 The AgRP neurons inhibit proopiomelanocortin (POMC) neurons by the concerted antagonistic action of GABA and NPY while sending collateral projections to many different brain areas corresponding to POMC projections.⁵³ POMC neurons, which are located in the ARC and nucleus tractus solitarius (NTS), are considered the main mediators of satiety signaling, along with CART peptides that inhibit food intake and increase energy expenditure.⁵⁴ Typically, POMC neurons integrate long-term obesity signals from the hypothalamus and short-term satiation signals from the brain stem, releasing α-melanocyte stimulating hormone (α-MSH) and β-melanocyte stimulating hormone (β-MSH) to activate the expression of melanocortin-3-receptor (MC3R) and MC4R in PVN. It decreases food consumption and enhances energy expenditure, thereby signaling mechanisms that promote thermogenesis and anorexia.^55,56 Conversely, the ablation of POMC neurons enhances anxiety-like behavior and increases the risk of obesity.⁵⁷

Fig. 2 Schematic of arcuate nucleus AgRP/NPY and POMC/CART signaling involved in the regulation of feeding activity. Active ghrelin secreted by the stomach is acylated for binding to its growth hormone secretagogue receptor-1α (GHSR-1α) in the ARC. Subsequently, the AgRP/NPY signalling pathway is activated, which escalates food intake mechanisms and decreases energy expenditure. Conversely, insulin and leptin produced from the pancreas and adipose tissue bind to specific insulin (InsR) and leptin (LepRb) receptors, respectively. This eventually activates POMC transcription for the regulation of food intake and energy expenditure. Furthermore, appetite hormones GLP-1, CCK, PYY, and OXM directly stimulate the vagus nerve to transmit satiety signal.

In addition to these two main appetite-regulating neural pathways, other neurons and glial cells also play an important role in the regulation of feeding. The palatability of food can drive feeding independent of AgRP neurons.⁵⁸ Obesity leads to the dysregulation of hypothalamic hunger neurons. A high-fat diet attenuates the response of AgRP neurons to an array of other nutritionally relevant stimuli.⁵⁹ Conversely, activating the ventrolateral periaqueductal gray GABAergic cells can mitigate obesity by restoring the miniature postsynaptic inhibitory currents and calcium responses.⁶⁰ Inhibition of the non-AGRP GABAergic neurons in the ARC can also reverse leptin-deficient obesity.⁶¹ Besides neurons, some non-neuronal cells in the ARC are also involved in the regulation of dietary energy balance, for instance, astrocytes are involved in the transport of nutrients and hormones from the circulation to the brain, glycogen storage, glucose sensing, synaptic plasticity, uptake and metabolism of neurotransmitters.^62,63 Glial cells in the ARC reduce ghrelin-induced food intake by regulating extracellular adenosine levels.^64,65 Insulin signaling in astrocytes co-control glucose sensing in the central nervous system and systemic glucose metabolism by regulating glucose uptake across the blood–brain barrier and participating in the integration of peripheral satiety signals.^66,67 Thus, astrocytes are expected to be a new target for appetite regulation in the future.

3. Appetite and the gut microbiota

The intestine is another organ, besides the brain, involved in appetite regulation. The vagus nerve provides parasympathetic innervation to the gastrointestinal tract, coordinating the complex interactions between the central and peripheral neural control mechanisms.⁶⁸ Satiety signals from nutrient stimulation or flora metabolism in the gastrointestinal tract are transmitted directly to the brain via the vagus nerve, driving or terminating host feeding behavior.^69,70 The gut microbiota influences the communication between the gastrointestinal tract and the brain (gut-brain axis) in a bidirectional manner, which might play a key role in the regulation of energy intake and satiety signaling.⁷¹ Intestinal endocrine cells (EEC) sense the gut luminal content and secrete hormones that modulate glucose and lipid metabolism, which ultimately affect satiety. Moreover, metabolites of the intestinal flora significantly affect the function of EEC.⁷² Nutrient infusion to the colon stimulates immediate bacterial growth, which usually lasts 20 minutes. Bacterial molecules and metabolites that depend on the growth phase are known to regulate the intestinal release of satiety hormones and inhibit feeding behavior.⁷³

One of the bacterial proteins, the caseinolytic peptidase B protein homolog (ClpB), which is a conformational antigen-mimetic of α-melanocyte-stimulating hormone (α-MSH), inhibits appetite through direct and indirect mechanisms. The ClpB-like gene function in gut microbiota, which is negatively associated with body mass index, waist circumference, and fat mass, is detected in lower abundance in subjects with obesity.⁷⁴ However, the injection of Escherichia coli protein in the stationary phase (increased ClpB expression) reduces food intake by activating the ARC of the anorexic arcuate nucleus and the central amygdala.⁷⁵ Muramyl dipeptide, another peptide produced by intestinal bacteria, can also cross the blood–brain barrier and activate Nod2 in the brain to inhibit the activity of GABaergic neurons directly in the ARC to reduce appetite.⁷⁶ Intestinal flora is an important factor in mediating host appetite. Significant differences in host feed intake and feeding behavior can be caused by different flora structures.⁷⁷ The deficiency of intestinal Bacteroides vulgatus and its metabolite pantothenate might lead to dietary sugar preference,⁷⁸ whereas probiotics administration leads to a positive improvement in feed intake and lipid and glucose metabolism.⁷⁹

4. Dietary nutrients and appetite regulation

Dietary nutrients play an important role in the process of appetite regulation. Mammals, birds, and insects have different appetite systems for macro-nutrients (carbohydrates, fats and proteins).⁸⁰ The influence of various nutrients on appetite is summarized in Table 1.

Table 1 Influence of dietary nutrients on appetite

Nutrient		Type	Influence on appetite	Ref.
Protein-associated nutrient	Protein	Whey protein	Slow gastric emptying and altered gut hormone secretion	87
		Casein	Increases satiety but does not affect subsequent energy intake	88
	Peptides	Fish protein hydrolysates	Anti-hyperglycemic and satiating effects	96
		Whey protein-derived peptides	Promote cholecystokinin secretion	97 and 98
		Soybean hydrolyzed peptides	Decrease leptin concentration and inhibit cholecystokinin release	99 and 100
		D3	Ameliorates leptin resistance and upregulates the expression of uroguanylin	133
	Amino acid	L-Glutamate	Reduces NPF secretion	105
		Cysteine	Promotes energy expenditure and suppresses food intake	106
		BCAAs	Stimulate leptin activity and GLP-1 levels and inhibit ghrelin levels	109
		Essential amino acids	Protein deprivation stimulates compensatory appetite for essential amino acids	111
		Non-essential amino acids	Reduce the portion size of intake but not the frequency	112
Carbohydrate		Resistant starch	Improves satiety and reduces food intake, but has no significant effect on appetite hormones	113–116
		Glycyrrhiza polysaccharide	Promotes hedonic eating behavior	117
		Ginseng polysaccharide	Promotes hedonic eating behavior	118
		Flaxseed polysaccharide	Suppresses appetite	119
Lipid		MUFA	Does not change any measures of appetite	134
		PUFA	Increases the desire to feed	128 and 129
		SFA	Promotes CCK secretion and increases peak PYY levels	130 and 131

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4.1 Dietary protein and hydrolysates regulate host appetite

4.1.1 Protein for appetite regulation. Proteins are known to be more satiating than other macronutrients.⁸¹ Oral exposure to protein-rich foods enhances the satiating capacity, indicating potential for the development of satiating food products.⁸² Short-term protein consumption suppresses appetite, decreases ghrelin production, and augments cholecystokinin and GLP-1.⁸³ Similarly, a high dosage of protein intake has been shown to improve appetite control and satiety in overweight or obese men during energy restriction-induced weight loss, promoting energy homeostasis and body fat management.^84,85 Dairy proteins, one of the main dietary protein sources, consist of 80% casein protein and 20% whey protein. Whey protein is more satiating in the short term, whereas casein protein satiates in the long term.⁸⁶ Whey protein intake slows down gastric emptying and alters gut hormone secretion, controlling energy intake and appetite.⁸⁷ Casein protein breakfast also increases satiety in a dose-dependent manner but does not affect subsequent energy intake.⁸⁸ Postprandial energy intake is reduced with the supplementation of milk protein compared with isocaloric drinks containing only whey or casein protein.⁸⁹ Furthermore, the protein lever hypothesis proposes that protein deficiency may increase energy intake and appetite.⁹⁰ Insufficient intake of protein stimulates the body to feed constantly to meet normal metabolic needs, resulting in excessive total energy intake. Highly processed foods are significant diluents of dietary protein, and the preference for protein promotes increased food intake, causing an energy excess.⁹¹ Percent dietary protein is negatively associated with total energy intake,⁹² and high protein intake enhances satiety and regulates the secretion of appetite-related hormones in the short term.^83,93

4.1.2 Peptides for appetite regulation. Peptides are smaller units of proteins that break apart. Some bioactive peptides act as potential anti-obesity agents and suppress appetite.^94,95 Fish protein hydrolysates have anti-hyperglycemic and satiating effects and therefore, can reduce calorie intake to prevent obesity.⁹⁶ Whey protein-derived peptides in cheese have demonstrated anti-obesity effects like increase in satiety and reduction in food intake by promoting cholecystokinin.^97,98 Pulses are good dietary sources for controlling appetite and reducing inflammation. Soybean-hydrolyzed peptides have been shown to decrease fat content, food intake, and leptin concentration, besides inhibiting cholecystokinin release.^99,100 However, it has also been reported that plant-based meat analogs may enhance gastrointestinal motility and appetite by interacting with specific volatile compounds and neuroactive ligand–receptor interaction pathways in the gastrointestinal tract.¹⁰¹

4.1.3 Amino acids for appetite regulation. Amino acids are the smallest units of peptides, and the differences in their composition, sequence, and structure directly affect the functions of the polypeptide chain. The differences in the amino acid compositions of whey protein and casein might cause different appetite regulation effects, increasing the plasma amino acids, CCK, and GLP-1.¹⁰² The appetite inhibition effect of whey protein may be related to the free amino acid profile in the plasma of the subjects, and specific amino acid concentrations affect the secretion of appetite hormones, such as GLP-1, insulin, and glucagon.^103,104 Beyond gustatory receptors and systemic amino acid sensors, enteroendocrine cells are believed to directly perceive dietary amino acids and secrete regulatory peptides. Dietary L-glutamate is formed by the metabotropic glutamate receptor mGluR to decelerate calcium oscillations in enteroendocrine cells, thereby reducing NPF secretion via dense-core vesicles and ultimately, inhibiting feeding.¹⁰⁵ Dietary cysteine intake increases the production of neuropeptide FMRFamide, which binds to cognate receptors to promote energy expenditure, suppress food intake, and reduce insulin resistance.¹⁰⁶ Compared with other amino acids, branched-chain amino acids (BCAAs: leucine, isoleucine, valine) play significant roles in regulating protein synthesis, metabolism, food intake, and aging.¹⁰⁷ Conversely, excessive accumulation of BCAAs can impair insulin signaling and cause hyperinsulinemia, leading to pancreatic β cell dysfunction.¹⁰⁸ Moderate intake of BCAAs can stimulate leptin activity (secretion or sensitivity) and GLP-1 levels, inhibit ghrelin levels and reduce subjective hunger,¹⁰⁹ while long-term BCAA intake may lead to hyperphagia and shorten the life span. Hyperphagia caused by the imbalance of dietary BCAAs and other amino acids may be related to 5-hydroxytryptophan deficiency, which can be effectively alleviated by tryptophan and threonine supplementation.¹¹⁰ Similarly, neuropeptide CNMamide was highly expressed in the enterocytes of Drosophila anterior midgut during protein deprivation; it could stimulate compensatory appetite for essential amino acids by acting on the CNMa receptors in neurons.¹¹¹ Supplementation of non-essential amino acids might also regulate feeding behavior as it activates hypothalamic orexin neurons to inhibit feeding, reducing the portion size of intake rather than frequency.¹¹²

4.2 Dietary carbohydrates and appetite regulation

Digestible carbohydrates (mainly starch) are usually absorbed after hydrolysis into glucose. Thus, this section mainly focuses on the effects of indigestible carbohydrates on appetite. By structural modification, starch can be converted to resistant starch with crystalline properties to inhibit digestion by gastrointestinal amylase. The role of resistant starch in insulin sensitivity improvement is well-established. However, the regulation of satiety by resistant starch is still controversial. Some studies have found that resistant starch can improve satiety and reduce food intake.^113,114 Meanwhile, other studies have found no significant effect of resistant starch on appetite hormones.^115,116 These contradictory results may be related to the type and intake of resistant starch. Moreover, non-starch polysaccharides (NSPs) may have a dual effect on appetite. Some NSPs are known to promote hedonic eating behavior, activate AgRp/NPY and inhibit POMC/CART neural circuits.^117,118 Most NSPs suppress appetite via physical effects in the gastrointestinal tract and mechanical and humoral stimulation to secrete satiety hormones.^119–121 The targeted regulation of intestinal flora by NSPs to promote changes in the SCFA and BA profiles, is also a potential mechanism of appetite regulation.^122,123

4.3 Dietary lipids and appetite regulation

High intake of dietary lipids is one of the important causes of obesity and overweight. The structure and form of fatty acids, such as chain length, saturation, and double bond position, affect host energy intake, body weight, and appetite balance.^124,125 Total intake of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) is associated with less weight gain, while trans-fat and saturated fatty acids (SFA) promote weight gain.¹²⁶ However, saturated fatty acids contribute more to satiety,¹²⁷ while ω-3 PUFA might moderately increase the desire to feed.^128,129 Compared with MUFA or PUFA, consumption of SFA promotes CCK secretion and increases peak PYY levels.^130,131 Paradoxically, other studies have shown that differences in fatty acid composition in high-fat diets do not lead to differences in appetite and intake.¹³² The types and specific mechanisms of fatty acids that affect appetite have not been fully revealed, demanding their further studies.

5. Dietary metabolites that regulate appetite

Various gut microbiota-associated metabolites are involved in the regulation of appetite (Fig. 3).

Fig. 3 Gut microbiota related metabolites involved in host appetite control. (I) Primary bile acids are metabolized by gut microbiota to form secondary bile acids, which together with SCFAs transformed by carbohydrate, stimulate FXR/TGR5 and GPR41/43 in enteroendocrine cells, respectively, to secrete appetite-regulating hormones GLP-1, PYY, and CCK. They circulate into the brain and suppress appetite. (II) Commensal bacteria can metabolize tryptophan (Trp) to produce tryptamine that affects the production and secretion of 5-hydroxytryptamine (5-HT) and some indole derivatives. 5-HT could act as a neurotransmitter that conveys signals from the gut to the brain and mediates appetite control. (III) Glutamic acid (Glu) could be metabolized by gut microbiota to produce GABA, a neurotransmitter that regulates appetite-related hormones CCK secretion. These gut microbiota metabolites pass through the blood and vagus circuits to hypothalamic neurons, regulating AgRp/NPY and POMC/CART circuits and controlling feeding.

5.1 Tryptophan metabolites

Tryptophan (Trp), which is metabolized into tryptamine and indole derivates by gut microbiota, can affect gut hormone secretion and cross the blood–brain barrier to directly activate satiety circuits in the brain.¹³⁵ Intragastric or intraduodenal administration of Trp inhibits subjective appetite and promotes the secretion of CCK, GLP-1, and PYY in a dose-dependent manner in healthy men but not in obese men.^136–138 Similarly, supplementation with 5% Trp increases satiety and reduces food intake in healthy rats.¹³⁹ However, several studies have shown inconsistent and contradictory results. Trp supplementation might promote appetite regulation via a serotonin pathway, enhancing feed efficiency, protein efficiency ratio, and reproduction performance.^140,141

5.2 GABA

GABA, a neurotransmitter produced by the metabolism of dietary glutamate, connects the gastrointestinal tract to the brain.¹⁴² The disruption of GABA signaling pathways inhibits postweaning feeding, NPY-induced hyperphagia and hunger associated with gastrointestinal motility.¹⁴³ Additionally, GABAergic inputs inhibit AgRP neurons and feeding, impairing sensory learning and food cue acquisition greatly.^144,145 However, research on gut microbial-derived GABA and appetite control is limited. Thus, further studies are needed to investigate the role of GABA in host metabolic health and its effects on the central nervous system to regulate appetite.

5.3 Dopamine

Dopamine (DA) is involved in normal and pathological food intake in humans.¹⁴⁶ Appetite-regulating hormones, such as insulin, leptin, and ghrelin, directly affect the dopamine reward pathway. These hormones activate receptors on dopamine-secreting neurons in the ventral tegmental area (VTA), which either stimulate (Ghrelin) or inhibit (leptin and insulin) dopamine signaling in the nucleus accumbens (NAc), thereby affecting the motivation to feed.^147,148 During food intake, immediate and delayed dopamine release occurs in distinct areas of the human brain. Food consumption triggers orosensory and post-ingestive dopamine release in humans, involving different neural pathways: orosensory integrative and higher cognitive centers.¹⁴⁹ Likewise, in the brain of a bee model, the need for food has been shown to elevate dopamine levels upon first arrival at the feeder and while departing from the food source and initiating a dance to communicate information about the food source.¹⁵⁰ Obesity and a high-fat diet alter dopamine transmission, leading to brain reward dysfunction and overeating. Within the reward system, dopaminergic and dopaminoceptive neurons are the key players involved in the transport, sensing, and metabolism of dietary lipids.¹⁵¹ The Roux-en-Y gastric bypass can also alter fat intake, promote the production of fat-satiety molecule oleoylethanolamide (OEA) in the lower small intestine to induce satiety, and increase dorsal striatal dopamine release via the vagus nerve.¹⁵²

5.4 SCFAs

SCFAs, such as acetate, propionate, and butyrate, are the main products of intestinal microbial fermentation of indigestible carbohydrates, and they are involved in host immune regulation, energy homeostasis and disease treatment.¹⁵³ The elevation of SCFAs in the colon stimulates the production of large amounts of hormones because their relevant receptors in different organs and tissues, such as G-protein-coupled receptors, free fatty acid receptor (FFAR) 2 and FFAR3, transmit neural signals, cumulatively inhibiting short-term appetite and energy intake.^154,155 Meanwhile, SCFAs reduce fat accumulation through appetite-related gene expression.¹⁵⁶ Acetate stimulates hypothalamic neurons by crossing the blood–brain barrier, directly suppresses appetite, and controls weight and insulin sensitivity.^157,158 Consumption of foods rich in propionate reduces blood glucose response and gastric emptying rates, increasing subjective satiety and reducing hunger, which is important for obesity management.^159,160 Colon delivery of propionate stimulates the release of PYY and GLP-1, reducing energy intake and preventing weight gain in overweight subjects.¹⁶¹ Butyric acid is an important regulator of energy homeostasis and has a significant impact on the regulation of thermogenesis and lipid and glucose metabolism.¹⁶² Butyrate supplementation inhibits the expression of neuropeptide Y by the appetite neurons in the hypothalamus, decreases neuronal activity in the NTS and dorsal vagal complex, and activates brown fat to enhance fat oxidation and improve energy metabolism.^163,164

5.5 Bile acid

Bile acid is the product of cholesterol modified by intestinal microbiota. It regulates nutrient absorption, mitochondrial function, inflammation response, appetite regulation, and energy homeostasis.¹⁶⁵ Knockout of the Cyp8b1 gene, an enzyme necessary for the production of 12α-hydroxylated bile acids, results in significant alterations in the composition of bile acids and lowers the levels of satiation-enhancing OEA in the jejunum.¹⁶⁶ Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5), which are receptors of bile acids, regulate the secretion of gastrointestinal hormones, including GLP-1, neurotensin and PYY, hepatic gluconeogenesis, glycogen synthesis, and energy expenditure.¹⁶⁷ Bile acids stimulate the secretion of appetite-regulating hormones, such as GLP-1, neurotensin, and PYY, by mediating basolateral intestinal TGR5, reducing AgRP/NPY release, and collaborating with CCK to enhance satiety.^168–170

6. Appetite regulation strategies

Diverse techniques, including dietary modulation to postpone gastrointestinal digestion and environmental modulation to improve the production of satiety hormones in consumers, have been implemented to manage the activity of appetite-related neurons and impact both food intake quantity and frequency.

6.1 Construction of slow-digestion nutrient delivery systems

A significant number of intestinal endocrine cells, including L cells, enterochromaffin cells, and P cells, are present near the terminal portion of the small intestine and colon. Undigested chyme moving to the distal colon may efficiently activate these intestinal endocrine cells to secrete satiation peptides (GLP-1 and PYY), hence diminishing hunger.^171–173 Nutrient delivery via a slow-digestion strategy can inhibit digestive enzyme activity, allowing nutrients to be transported to the distal ileum and colon slowly, promoting the secretion of appetite hormones and reducing food intake.^174,175 Compared with fast-digestible foods, slow-digestible foods allow for more frequent nutrient interaction with the gastrointestinal tract and longer transport time, thereby increasing the stimulation of endocrine cells at the terminal end of the small intestine and promoting the secretion of satiety hormones (Fig. 4). The consumption of slow-digested starch blunts post-meal fluctuations in blood glucose and insulin, thereby prolonging energy supply and satiety and suppressing the expression of appetite-stimulating neuropeptide genes associated with the gut-brain axis.^174,176,177

Fig. 4 Effect of slow-digestion nutrient delivery systems on appetite regulation. Macronutrient degradation produces small-molecular nutrients, such as long-chain fatty acids (LCFAs), oligosaccharides, monosaccharides, SCFAs, and amino acids, which stimulate the intestinal endocrine cells to produce satiety hormones (PYY, GLP-1, CCK, and oxyntomodulin (OXM)). Compared with the fast digestion of food, the slow digestion of nutrients extends the chyme transport time and increases the stimulation of distal intestinal endocrine cells to signal satiety, thus promoting appetite regulation.

6.2 Influence of chyme physicochemical properties on appetite

The physicochemical characteristics of chyme significantly influence satiety (Fig. 5). Food milling and cooking disrupt the microstructure of fibers and alter the physicochemical characteristics, hence enhancing the digestibility of starch and the breakdown of plant-derived chemicals.¹⁷⁸ The physicochemical properties of dietary fiber (solubility, viscosity, fermentability, etc.) determine its function in the gastrointestinal tract and can impact nutrient utilization, intestinal motility, fecal formation, and microbial specificity.¹⁷⁹ Plant-derived dietary fibers with a relatively dense and orderly physical structure lead to slow digestion and fermentation in the gut via a prolonged fermentation process and facilitate the production of butyrate.¹⁸⁰ The viscosity of the dietary fiber impedes the gastric emptying rate of chyme and nutrient absorption in the small intestine while also augmenting perceived fullness.^181,182 For example, different structures and physicochemical properties of konjac glucomannan (KGM) have distinct satiety-enhancing effects. The viscous and gel properties of KGM significantly delay the rate of gastric emptying and stimulate satiety via the vagus nerve.^183–185 The change in appetite caused by the effects of the physical and chemical properties of dietary fiber profoundly affects host glucose and lipid metabolism.¹⁸⁶ It is an effective measure to modify the physical and chemical properties of food, promote the interaction between chyme and the host gastrointestinal tract, increase the secretion of appetite hormones, and enhance satiety.

Fig. 5 Influence of chyme physicochemical properties in the gastrointestinal tract on appetite regulation. Tough foods promote saliva production and stimulate satiety nerves during oral mastication. In the stomach, viscous chyme increases gastric tension, triggers the vagus nerve to transmit satiety signals to the brain, and delays gastric emptying. In the small intestine, viscous chyme delays the absorption of nutrients, blunts the blood glucose response, and stimulates the secretion of satiety hormones in the distal small intestine. Finally, anaerobic fermentation metabolites in the large intestine are promoted to regulate insulin sensitivity and appetite response.

6.3 Appetite regulation based on dietary rhythm

The circadian rhythm significantly affects the temporal regulation of food intake and metabolism, and the related feeding habits regulate the appetite level of the subjects.¹⁸⁷ Unusual feed timings might disrupt the circadian system, resulting in digestive enzyme expression disorders. High caloric intake at breakfast could cause significantly more weight loss than those assigned to dinner.¹⁸⁸ The thermogenic effect of breakfast foods exceeds that of dinner, whereas dinner foods have a greater probability of elevating blood glucose and insulin levels. A low-calorie breakfast may result in increased hunger and cravings for sweets during the day.¹⁸⁹ Conversely, compared with evening energy intake, morning energy intake significantly inhibits food craving and improves satiety and hunger management.^190,191 A high-calorie breakfast significantly reduces mean hunger scores in overweight and obese women. Thus, it is helpful for the management of obesity and metabolic syndrome.¹⁹² Similarly, eating breakfast and avoiding late-evening snacking sustains lipid oxidation and potentially improves metabolic outcomes.¹⁹³ It is suggested that people with irregular diets due to long-term overtime work schedule their meal times reasonably to manage obesity and maintain normal glycolipid metabolism. Therefore, maintaining a suitable feeding schedule and energy metabolism is also necessary for appetite regulation. Constructing slow-digestion nutrient delivery systems, regulating chyme physicochemical properties and increasing morning calorie intake are effective strategies to improve appetite, hormone levels and satiety in obese subjects (Table 2).

Table 2 Dietary strategies for appetite regulation

Dietary strategy	Target	Effect on satiety
Slow-digestion nutrient delivery systems	Distal colon	Stimulate the secretion of appetite hormones
Chyme physicochemical properties	Mouth, stomach, and intestine	Delay gastric emptying and slow down the digestion and absorption of nutrients
Dietary rhythm	Brain	Influences digestive enzyme activity

---

7. Conclusion

At present, the incidence of obesity-related chronic metabolic diseases is rising at an alarming rate. Dietary management methods to improve satiety and control appetite are widely recommended and considered safe options. AgRp/NPY that promote feeding and POMC/CART that inhibit appetite are two homeostasis neural circuits in the arcuate nucleus regulating hunger. Food palatability can drive the hedonic feeding mechanism of the AgRp neurons. Furthermore, this study also reviews the role of intestinal flora in appetite regulation and satiety contribution. Dietary nutrients are the main driving forces that regulate appetite signals. The contribution of protein nutrients for the stimulation of satiety hormones and appetite neural circuits has important guiding significance for satiating foods. In contrast, the satiety effects of different fatty acid types produced from lipid foods and carbohydrates are still controversial. The small-molecular-weight metabolites of dietary nutrients in the digestive tract, such as dopamine, short-chain fatty acids, and bile acids, are considered potential appetite regulators as they combine with corresponding receptors and participate in the regulation of appetite neural circuits. Additionally, dietary modifications to prolong chyme transport time and change its physical and chemical properties, as well as dietary rhythm regulation, are also highlighted as effective appetite regulation strategies. However, there are still many deficiencies for subsequent research. Many conclusions presented in this review are derived from animal experiments, and there is a lack of necessary evidence for their translation in human studies. Secondly, this review focuses primarily on obesity induced by gluttony, without considering the influence of various factors such as region, religion, dietary culture and living habits. Therefore, to address the need for precision nutrition in the future, designing distinct dietary plans and appetite regulation strategies suitable for different populations is crucial for the prevention of chronic metabolic diseases.

Author contributions

Pengkui Xia, Tao Hou, and Jing Li conceived the study and designed the search strategy, synthetized information and wrote the manuscript. Yudie Yu, Wanxu Yu, Mahmoud Youssef, and Bin Li revised the manuscript. All authors read and approved the final version of the manuscript.

Data availability

All relevant data are included within the manuscript.

Conflicts of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

This work was financially supported by Hubei Provincial Natural Science Foundation for Distinguished Young Scholars (2022CFA085) and HZAU-AGIS Cooperation Fund (SZYJY2022020).

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