Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach

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Exercise is now considered as a medicine and meritoriously adjunct intervention in improving the condition of metabolic diseases. This overview may contribute to developing exercise-based strategies for managing obesity. Sports scientists and fitness instructors in collaboration with other healthcare professionals may use the information provided in this study to design a personalized exercise program to suppress appetite and augment weight loss. The mechanisms proposed in this paper might be amalgamated to other approaches, such as dietary supplementations and behavioral therapies, to comprehensively optimize obesity management.

Abstract

Exercise suppresses appetite in individuals with obesity irrespective of the type, duration, or intensity of the exercise. This effect is mediated through various physiological and biochemical mechanisms. Exercise influences appetite-regulatory hormones such as ghrelin and leptin, reducing hunger signals. Additionally, exercise generates metabolites and myokines, along with hepatokines, which modulate appetite suppression. Brain-derived neurotrophic factor (BDNF) is also implicated in modulating appetite. Changes in eating behaviors, gastric motility, and gastric emptying further contribute to a reduced appetite. Mental stress and body temperature alterations during exercise can also impact hunger levels. This review synthesizes current evidence and provides specific biochemical, metabolic and molecular mechanisms of how exercise and obesity affect appetite regulation. More specifically, it is extensively discussed the effect of exercise and obesity on: (1) endocrine mediators (hepatokines, metabolites, myokines, and neurotrophins); (2) physiological modulators (gastric emptying and body temperature); and (3) behavioral influences (eating patterns and visual food cues) in association with appetite regulation. Collectively, these factors highlight the complex interplay between physical activity and appetite regulation, offering insights into potential therapeutic strategies for managing obesity through exercise.

1. Introduction

Obesity levels have increased exponentially, making it a global epidemic; obesity increases the risk of developing comorbidities, including type 2 diabetes mellitus, cardiovascular diseases, hypertension, and liver and endometrial cancers [1,2]. Obesity is a consequence of long-term changes in energy balance in which energy intake exceeds energy expenditure [3], where a mismatch of lower than 0.5% in caloric intake over caloric expenditure can result in weight gain [4]. This imbalance between energy intake and expenditure likely results from disrupted mechanisms regulating appetite and eating behaviors [5]. Appetite is influenced by a multiplicity of physiological, psychological, and environmental factors that are integrated in the brain to impact eating behaviors [6,7]. Signals from the hypothalamus normally regulate appetite and energy intake; the hypothalamus and, in particular, the arcuate nucleus (ARC), receive and processes neuronal, metabolic, and endocrine signals from various tissues and organs to establish energy homeostasis by maintaining energy intake and expenditure [8]. For further discussion concerning the neuroanatomy and physiological function of ARC, refer to relevant studies in the literature [9,10,11,12,13,14]. Briefly, the brainstem receives vagal efferent neurons from the gastrointestinal tract and acts as a platform for amalgamating endocrine and neuronal signals [15]. Although most peripheral signals influencing the appetite control system originate from the gastrointestinal tract, other organs, such as adipose tissue, metabolites [16,17], and even external stimuli from food and the external environment, such as restraint, disinhibition, and hedonic sensation [18,19], also regulate appetite and energy intake. Exercise influences and alters these appetitive signals [20,21] and is considered a therapeutic treatment and an adjunct intervention against obesity and its negative health consequences [22].

Physical activity and exercise reduce obesity by regulating mean body weight and adipose tissue function [23]. Increased energy expenditure induced by exercise creates a negative energy balance without changes in compensatory energy intake following acute and chronic exercise [24,25]. Physical activity is a mechanical and a metabolic stress that instigates some time-dependent processes to produce morphological and functional changes, leading to either acute and chronic adaptations according to the exercise type, intensity, and duration [26]. Endurance or aerobic training causes a transition of muscle fiber type from IIb to more oxidative types IIa and I, which are characterized by increases in mitochondrial size and number, an improved capillary network surrounding each fiber type, and elevated levels of carnitine palmitoyl transferase. These adaptive changes stimulate the β-oxidation of fat and cause increases in energy expenditure [27,28,29]. On the other hand, resistance/strength training leads to increased muscle size, which promotes protein synthesis, and increases in the resting metabolic rate, resulting in weight loss [30,31].

Influencing energy intake and appetite regulation is another mechanism through which acute and chronic exercise partly alters energy balance and body weight [32,33,34]. Acute exercise on a treadmill at 60% VO_2peak for 60 min reduces appetite and energy intake in individuals with obesity [35]. Some of these exercise effects cause fluctuations in the concentrations of appetite-regulatory hormones, such as peptide YY (PYY), ghrelin, glucagon-like peptide (GLP), among others [21,36]. Chronic [32,37] and acute [32] exercise changes subjective and homeostatic influences of appetite to cause a sensation of postprandial fullness. Chronic exercise modulates the sensitivity of appetite control by moderating eating or eating behaviors, amending the responses to hunger signals, postprandial satiety signals, and modulating hedonic responses [38,39,40]. This review systematically examines the mechanistic interplay between exercise, obesity, and appetite regulation. Specifically, we (1) decipher the neuroendocrine physiology of appetite control, focusing on hypothalamic and brainstem integration of peripheral signals (e.g., gut hormones, adipokines, and metabolites); (2) elucidate how obesity can influence appetite through changes in the main factors involved in appetite control; (3) explain acute and chronic exercise-induced adaptations in appetite regulation; (4) identify critical gaps in the current research, especially individual variability in appetitive responses and the distinct responses of main appetitive markers to various exercise types; and, (5) finally, we recommend future directions to be considered by investigators who are interested in working in this research realm.

2. Exercise and Appetite-Regulatory Hormones

Adipose tissue is a metabolically active organ that undergoes structural and functional changes in response to dietary changes and food intake [41]. Most anti-obesity treatments address the suppression of appetite to curb excess energy intake [42,43], with changes in lifestyle and regular exercise being effective non-pharmacological interventions in managing adiposity and related diseases [44]. Regular physical activity expedites weight management by increasing energy expenditure and regulating appetite hormones (orexigenic and anorexigenic) [23,45], including leptin, ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), and cholecystokinin (CCK) [46]. These hormones are synthetized and secreted from peripheral tissues (intestine and adipocytes [6]) and interact with brain centers (hypothalamus) monitoring and regulating feeding and satiety behaviors [47]. Although a sedentary lifestyle disturbs the mechanisms responsible for appetite regulation [48], exercise regulates appetite and appetite-regulating hormones in sedentary individuals with obesity [30,49]. In this context, three different intensities of resistance training improve body weight and fat; reduce leptin, CCK, and GIP; and increase ghrelin, adiponectin, PYY, and GLP-1 [50]. However, the effects of endurance training on these appetite hormones may be different.

Ghrelin is released by gastric oxyntic cells in response to fasting [51]. Plasma levels of the orexigenic hormone ghrelin are reduced in obesity [52] (Figure 1). Resistance exercise increases ghrelin levels, which may be mediated in part by catecholamines in an exercise-intensity-dependent manner [53] (Figure 2). Elevated ghrelin levels following exercise in individuals with obesity may represent a compensatory mechanism to stimulate appetite and counteract weight loss [54]. Ghrelin administration increases the frequency of meals to cause weight gain. Acute bouts of exercise modulate blood levels of ghrelin, with some studies reporting that ghrelin release is suppressed during running and resistance exercise [31,55,56]. Exercise intensity and duration are the main determinants of ghrelin response to acute exercise [57]. Rope jumping (3 × 10 min/5 min interval) and exercise on a cycle ergometer (3 × 10 min/5 min interval) reduce ghrelin release [58]. The main mechanism by which ghrelin is reduced by acute exercise may partly be related to its synthesis, where exercise lowers conversion to its active form by modulating ghrelin-O-acyltransferase (GOAT) [59,60] (an enzyme that catalyzes its post-translational modification by adding a medium-chain fatty acid to its third N-terminal amino acid residue) [61], increased sympathetic output, elevated gastric mucosal ischemia via the redistribution of blood flow from splanchnic circulation to skeletal muscles during exercise [37], and increased growth hormone (GH) secretion, which exerts negative feedback on ghrelin production [62] (Figure 2).

Exercise intensity is another factor that antagonizes ghrelin release. High-intensity exercises increase circulatory levels of lactate (Figure 2), which in turn suppress ghrelin production by binding to G-protein-coupled receptor 81 (GPCR81) in gastric cells [63]. Paradoxically, training programs can increase the ghrelin concentration mainly as a result of weight loss [64,65]. Some studies reported that increased ghrelin levels following long-term training and in individuals with obesity were higher than after short-term training and in individuals with normal body weight [66,67]. Training programs that caused no changes in body weight failed to increase ghrelin levels [68,69].

Other studies indicate that acute and chronic exercises lower leptin levels [70,71,72], which may partly be ascribed to abated body fat and increased muscle mass (Figure 2). Leptin is mostly synthesized in and released from adipose tissue, and exercise-induced reductions in its concentration induced a compensatory response to increases in appetite [73,74].

As one of the major signals of energy status, leptin levels impact appetite, satiety, and motivational behaviors (e.g., feeding and foraging behaviors) related to the maintenance of energy reserves. Plasma levels of leptin correlate with energy reserves, particularly triglycerides (TGs) stored in adipose tissue. The brain responds to circulatory leptin, where high leptin levels signify high energy reserves and low leptin levels indicate low energy reserves, allowing the organism to adapt to starvation through a variety of metabolic, endocrine, neurobiochemical, and behavioral changes [75]. Leptin receptors (LEPRs) are expressed by a variety of brain areas related to feeding [76,77].

There is decreased sensitivity to leptin, or rather, leptin resistance in obesity, resulting in an inability to detect satiety despite high energy stores and high circulating levels of leptin [78]. Leptin resistance in the brain of individuals with obesity has been widely documented and is associated with both impaired intracellular signaling pathways [79,80,81,82,83] and reduced expression of regulatory proteins, including suppressor of cytokine signaling (SOCS) proteins [84,85,86,87].

The effects of a long-term diet and exercise program (6 months) on plasma leptin concentrations was studied in 21 men and women with obesity. Weight loss decreased plasma leptin concentrations, indicating improved leptin sensitivity (Figure 2). The decrease in plasma leptin concentrations was correlated with reductions in body weight and body fat mass [88]. Although exercise reduces circulatory leptin levels, the improvement in leptin signaling and its sensitivity in the central nervous system offset such reductions. In an investigation by Abbenhardt et al. (2013), it was reported that aerobic exercise (1 h/day, 5 days/week, for 12 months), compared with high-intensity exercise, lowered both body weight and leptin levels and promoted hypothalamic leptin sensitivity [89]. Similarly, a reduction in leptin concentration occurred after 5 months of aerobic exercise [90] and 6 months of resistance exercise [70]. The underlying mechanisms of reductions in leptin levels following exercise may be due to increases in growth hormone and testosterone [91,92] and reduced cortisol levels [93,94] (Figure 2). A reduction in amplitude in the fluctuation in leptin levels occurs following exercises with a long duration (more than 60 min) that result in an energy imbalance [95,96]. Thus, there is also a negative correlation between the rate of energy expenditure and circulatory leptin concentration.

While exercise often leads to a reduction in circulatory leptin levels due to a decreased body fat content, it can enhance leptin sensitivity in the brain, particularly in the hypothalamus [97,98] (Figure 2). Improved hypothalamus sensitivity to leptin that occurs by reducing inflammation, enhancing insulin sensitivity, and promoting neurogenesis and synaptic plasticity boosts its ability to regulate appetite and energy balance [97,99,100]. Upon binding to receptors, primarily the long isoform receptor (ObRb) located in the hypothalamus, leptin activates several signaling pathways, with the most notable being the JAK2/STAT3 pathway, which leads to the transcription of genes that promote satiety and reduce food intake [101]. Among the genes induced by this pathway are POMC, suppressor of cytokine signaling 3 (SOCS3), and brain-derived neurotrophic factor (BDNF) [85,102]. Additionally, leptin inhibits excitatory neurons (AgRP/NPY neurons) in the hypothalamic ARC that stimulate appetite and activates inhibitory neurons (POMC neurons) that suppress appetite [103]. Leptin also affects the brain’s reward system by suppressing the activity of dopamine neurons in the hypothalamus, which reduces the reward value of food, to further decrease food intake [104] (Figure 2).

There is an inverse relationship between fat mass and adiponectin levels, so as fat mass increases, adiponectin levels decrease (Figure 1). Adiponectin is primarily produced and secreted by adipose tissue, and its secretion is regulated by the size and number of adipocytes. Adipose tissue in individuals with obesity is characterized by adipocyte hypertrophy, inflammation, and insulin resistance, which reduces adiponectin production and secretion [105]. In contrast, weight loss increases adiponectin levels in individuals with obesity by reducing adipose tissue mass, improving adipose tissue function, and reducing inflammation, culminating in increases in adiponectin production and secretion [106]. Exercise training increases circulatory adiponectin levels through several molecular mechanisms [70,107]. Adiponectin is primarily produced and secreted by adipose tissue but can also be produced by skeletal muscle and other tissues [108]. Exercise stimulates the production and secretion of adiponectin from both adipose tissue and skeletal muscle, leading to increased circulatory adiponectin levels (Figure 2). Exercise stimulates the AMP-activated protein kinase (AMPK) pathway in skeletal muscle [109], which in turn enhances glucose uptake and fatty acid oxidation in skeletal muscle, leading to improved insulin sensitivity and reduced fat accumulation in adipose tissue and increased adiponectin levels. Importantly, exercise stimulates the peroxisome proliferator-activated receptor gamma (PPARγ) pathway in adipose tissue [110], which enhances insulin sensitivity and reduces inflammation in adipose tissue, resulting in increased adiponectin levels. Exercise induces the production and secretion of myokines (cytokines produced by skeletal muscle in response to exercise), such as IL-6, that stimulate adiponectin production and secretion from adipose tissue (Figure 2). The decreased production of pro-inflammatory cytokines and increased production of anti-inflammatory cytokines, such as IL-10, are additional mechanisms by which exercise increases adiponectin levels [111].

Adiponectin affects appetite via actions on brain centers regulating food intake. Adiponectin interacts with its receptors expressed on some neurons in several regions of the brain, including the hypothalamus [112,113], to regulate and modulate the expression of neuropeptides such as AgRP and POMC [113,114]. Adiponectin increases POMC expression and decreases AgRP expression by activating the AMPK pathway in hypothalamic neurons, leading to a decrease in food intake and an increase in energy expenditure [115]. In addition, adiponectin also inhibits the activity of orexin neurons in the hypothalamus, which are involved in the regulation of food intake and arousal [116,117] (Figure 2). There are two types of orexin neurons, orexin-A and orexin-B, which release excitatory neuropeptides produced by some cells in the lateral and posterior hypothalamus, although they send projections throughout the brain. Orexin peptides bind to two G-protein-coupled orexin receptors, OX1 and OX2; orexin-A binds to both OX1 and OX2 with approximately equal affinity, while orexin-B binds mainly to OX2 receptors [118,119]. The inhibition of orexin neurons by adiponectin decreases food intake and increases energy expenditure. Adiponectin also modulates the gut–brain signaling axis by acting on the vagus nerve, which acts as a link between the gut and the brain [120,121]. Adiponectin-mediated increases vagal activity, leading to decreased food intake and increased energy expenditure (Figure 2).

Both acute [moderate-intensity exercise with a 50–75% VO2max and high-intensity exercise with a 85–90% maximal heart rate] [122,123,124,125] and chronic exercise [12-wk supervised chronic program] [40] increase GLP-1 levels in healthy individuals and those with obesity. GLP-1 is a peptide hormone secreted by enteroendocrine L-cells in response to nutrient ingestion. The primary site of GLP-1 secretion is the distal ileum and colon, with smaller amounts produced by the proximal intestine [126]. GLP-1 has an important role in regulating glucose homeostasis, food intake, and gastrointestinal motility [127,128,129]. This peptide has higher fasting and postprandial concentrations in individuals with obesity (Figure 1) that are positively correlated with insulin levels and a homeostasis model assessment of insulin resistance (HOMA-IR) [130,131]. GLP-1 activates the GLP-1 receptor (GLP-1R), a G-protein-coupled receptor (GPCR) that is widely expressed in various tissues including the pancreas, brain, gastrointestinal tract, heart, and adipose tissue. Upon binding to GLP-1R, GLP-1 activates intracellular signaling pathways, including the cyclic adenosine monophosphate (cAMP) and PI3K/Akt pathways [132,133]. Exercise increases circulating levels of GLP-1, which then binds to GLP-1R in areas of the brain regulating food intake and reward, such as the hypothalamus (paraventricular and supraoptic nuclei) and the mesolimbic dopamine pathway [132,134]. The L-cells of the ileum and colon secrete GLP-1, which then signals the brainstem and appetite-monitoring hypothalamic centers (Figure 2). GLP-1 signaling in these areas decreases appetite and food intake and may also contribute to the regulation of mood and reward [135,136,137]. Exercise increases GLP-1 levels partly by activating the sympathetic nervous system and releasing catecholamines [138] and by releasing IL-6 from contracting muscles [139,140] (Figure 2).

The enteroendocrine cells in the duodenum releases CCK in response to acidic foods [47,141]. CCK has physiological roles as a neuropeptide in the central nervous system to modulate satiety [142] and anxiety [143] and in the gut to stimulate the digestion of fats and proteins [144,145]. CCK is the most abundant neuropeptide in the central nervous system [146,147] and mediates satiety by acting on CCK receptors, which are GPCRs and exist as two subtypes, CCKA and CCKB [148,149], which are distributed widely in the central nervous system [150]. Decreased rates of gastric emptying [151,152] and the stimulatory effects of the vagus nerve [153,154], which opposes the effects of ghrelin [155], are pathways by which CCK suppresses hunger (Figure 2). The plasma levels of CCK in individuals with obesity correlate with body mass so that weight loss is accompanied with reduced production and release of CCK [156] (Figure 1). The levels of CCK are reduced in participants with obesity following an 8-week program of body weight reduction [156]. The reduction in CCK levels after weight loss may partly be a compensatory response to increased appetite. The levels of CCK increase soon after acute exercise in non-obese individuals and are maintained for up to 2 h after exercise [157,158], likely as a mechanism to suppress hunger after exercise [36]. The findings related to exercise training on CCK levels are variable, with reports of increases after intensive or hypoxia training [158,159] and a reduction in runners after high-intensity training [160], and even no changes following 12-week training in individuals with obesity [161]. More extensive studies are needed on the effects of acute and chronic exercise CCK levels in subjects with obesity.

Peptide YY (PYY), a short peptide secreted by L-cells in the ileum and colon, exhibits postprandial elevation (particularly following fatty meal consumption) and declines during fasting periods. The direct injection of PYY into the central nervous system reduces appetite [162,163]. PYY is produced by neurons in the gigantocellular reticular nucleus of the medulla oblongata [164] and exerts its actions by binding to NPY receptors NPY1R, NPY2R, NPY4R, and NPY5R [165,166]. The hippocampus and hypothalamus have a high density of these receptors, with three subtypes [NPY1R, NPY4R, and NPY5R] regulating food intake [167]. Two hours after the infusion of PYY led to 30% and 31% reductions in caloric intake in individuals with obesity and lean subjects, respectively [168]. Low postprandial concentrations of PYY are measured in individuals with obesity and may aid in unchecked food intake [169,170] (Figure 1). However, moderate-intensity aerobic training for 12 weeks increased postprandial PYY levels in men and women with obesity [40] (Figure 2). Changes in PYY concentrations after chronic exercise are variable in persons with obesity, with some studies reporting no changes [30,65,171], and other studies measuring increases in PPY levels after a long-term exercise period of more than 12 weeks [172,173]. Several studies reported increased levels in the PYY hormone in non-obese females and males after acute exercise [174,175,176]. Increased PYY levels following exercise induces a feeling of satiety and reduces food intake.

3. Exercise and Appetite-Reducing Metabolites, Myokines, and Hepatokines

Several metabolites have been identified in response to endurance, resistance, and combined exercise by using metabolomics analysis [177,178]. Lactate is a small molecule with roles ranging from being a signaling molecule to being an alternative fuel source [179]. In addition, lactate also suppresses appetite after exercise [63,180,181]. Muscles release more lactate after high-intensity exercises (near maximal, maximal, or supramaximal), which leads to greater reductions in appetite and energy intake [181,182] (Figure 3). Lactate is released into the circulation and exerts its anorexigenic function through several mechanisms:

(a) It hinders ghrelin production from gastric cells. Lactate binds to GPCR81, which is highly expressed on ghrelin-releasing gastric cells [183] to inhibit ghrelin release from gastric mucosal cells [37,181,183,184]. Additionally, lactate inhibits the activation of GOAT, which alters ghrelin activation [183].

(b) It modulates hypothalamic neuropeptide release. Lactate produced by exercising muscle is secreted into the circulation through monocarboxylate transporters (MCTs), which allow for bidirectional exchange between tissues/cells and is extensively expressed on hypothalamic orexigenic and anorexigenic neurons, enabling lactate to activate energy intake-regulating signaling pathways such as STAT3, protein kinase B (Akt) [185,186,187], and inactivating AMPK [188]. AMPK is a leading factor in regulating energy intake [189], and its inhibition activates acetyl-CoA carboxylase (ACC) to increase hypothalamic malonyl-CoA concentrations, resulting in decreased and increased NPY/AgRP and POMC neuropeptides, respectively [186,188,190].

(c) It suppresses hypothalamic ghrelin signaling. Ghrelin upregulates the expression of NPY/AgRP neuropeptide (accompanied with increased appetite) by acting on growth hormone secretagogue receptors (GHSRs), which are expressed in hypothalamic nuclei related to appetite [191,192], and antagonizing GHSRs dampens appetite. Lactate administration (0.3 mg/mL) to HEK-293a cells exhibiting an overexpression of GHSRs reduced GHSR signaling [193] and may underlie the effects of lactate in mitigating ghrelin signaling and NPY/AgRP expression to inhibit appetite [190,193].

Lactate is a precursor in the synthesis of N-lactoyl-phenylalanine (Lac-Phe), a metabolite with anorexigenic effects in rodents [34]. Lac-Phe is an enzymatically conjugated product of lactate and phenylalanine amino acid that is catalyzed by carnosine dipeptidase II (CNDP2), which is expressed by macrophages, other immune cells, and in epithelial cells the of kidney, gut, and lung [194]. Exercise, especially at high intensity, increases circulatory levels of Lac-Phe in humans and predicts the loss of adipose tissue in individuals with overweight/obesity [34,194,195] (Figure 3). Acute administration of Lac-Phe in obese mice suppresses energy intake over 12 h by 50% [34]. The plasma levels of Lac-Phe increase after endurance, resistance, and sprint exercises in humans, racehorses, and mice, with increases in sprint and resistance exercises being greater than those after endurance exercise [34]. Plasma increases in Lac-Phe correlate with lactate concentrations [34]. Thus, increased circulating levels of Lac-Phe in response to intense exercise can temporally suppress appetite after intense exercise [34]. The limited investigation on this metabolite has not produced details on its mechanisms of action. Circulating levels of Lac-Phe during intense exercise targets GPCRs expressed on neurons in the central nervous system involving regulating appetite (Figure 3).

Myokines (muscle-derived factors), which have a role in reducing and maintaining body weight, are produced in response to energy demands and during cell proliferation and differentiation [196,197,198]. Some myokines inhibit eating behaviors and energy intake and are thought to be beneficial in obesity suppression and treatment. Inteleukin-6 (IL-6) is a myokine and also a pro-inflammatory cytokine that partly mediates the effects of exercise on appetite suppression and energy intake [197,199,200,201]. The inhibition of IL-6 by pharmacological agents, such as tocilizumab, triggers an obesogenic state [202], while the overexpression of IL-6 [203] and its central or peripheral administration results in hunger and anorexigenic effects [204,205,206]. Metabolic diseases such as obesity and type 2 diabetes are associated with increased inflammation and pro-inflammatory cytokine levels such as IL-6 released by adipose tissue [207,208,209] (Figure 1). In contrast to adipose tissue and plasma, IL-6 levels in the central nervous system (CNS) are dampened in obesity, suggesting different roles of peripheral and central effects of IL-6 in obesity [205,210] (Figure 1). In contrast, other studies report constant increases in hypothalamic IL-6 in response to an obesogenic diet [211,212].

Exercise also alters the expression and concentration of IL-6, as shown in individuals with normal weight and adiposity following high-intensity exercise, where IL-6 levels are negatively correlated with appetite and energy intake [213] (Figure 3). Exercise increases circulatory IL-6 concentrations in intensity-, duration-, and glycogen content-dependent manners [181,214]. Adipose tissue and immune cells release IL-6 in obesity and autoimmunity, respectively, while skeletal muscles are the main source of circulatory levels of IL-6 during exercise bouts, which peak immediately post-exercise and return to baseline levels ~2–3 h after exercise cessation [215,216]. The increase in IL-6 levels is dependent on exercise duration, intensity, and muscle mass involved [214,216]. Several mechanisms have been proposed by which IL-6 transcription and expression responds to exercise, including the following: (1) Muscle contraction is accompanied by increases in intracellular and nuclear calcium that activate PI3K to stimulate IL-6 transcription [217] (Figure 3). (2) The production and secretion of IL-6 during exercise is regulated by the muscle glycogen content and glucose ingestion [218,219,220]. The expression of IL-6 mRNA and its protein in working muscles is diminished when intramyocellular glycogen stores decline, so IL-6 serves as an energy sensor [218,221] (Figure 3). Although acute exercise elevates plasma IL-6 concentrations, regular exercise lowers the IL-6 baseline levels of both circulating and muscle mRNA levels [222]. Exercise increases the expression of IL-6 receptors (IL-6R) in muscle, suggesting increased muscle sensitivity to IL-6 [223].

Increased energy demands during exercise stimulate IL-6 production by contracting skeletal muscles and increase the plasma levels of IL-6 [215,224,225,226]. IL-6 activates membrane-bound gp130 receptors to stimulate JAK and the phosphorylation of tyrosine in the gp130 cytoplasmic domain, leading to its activation and phosphorylation, followed by the formation of STAT dimerism and then translocation to the nucleus to increase the transcription of some genes involved in inflammation, immune response, cell survival, and tissue repair [227,228,229].

The CNS is the main site where IL-6 exerts its metabolic and anorexigenic effects [230,231]. High concentrations of circulatory IL-6 can access brain areas regulating appetite and energy intake, such as the hypothalamus after crossing the BBB [232]. Exercise increases BBB permeability by downregulating tight junction proteins and astrogliosis [233]. Additionally, IL-6 is expressed centrally by astrocytes, microglia, and neurons [234,235,236]. Some mechanisms by which peripheral and central IL-6 influence appetite and energy intake include the following:

• Increases in systemic IL-6 levels promote the production and secretion of GLP-1 and PYY from intestinal L-cells and pancreatic α-cells [139,181,237], which has a negative correlation with appetite and energy intake [139,181,238] (Figure 3). Increased GLP-1 levels elevate insulin secretion and improve glucose tolerance while also having anti-obese effects by acting on the hypothalamus [139,140,239,240]. Peripherally produced GLP-1 crosses the BBB to bind to its receptors on the hypothalamus to increase the expression and release of POMC neuropeptide, followed by diminished energy intake and body weight [140,241,242]. Additionally, central GLP-1 stimulates the expression of hypothalamic IL-6 and IL-6 receptor α (IL-6Rα) mRNA by neurons and glial cells to increase and decrease, respectively, the expression of POMC and NPY/AgRP neuropeptides, which in turn cause hypophagic effects and appetite suppression [140,243,244,245,246] (Figure 3).
• Hypothalamic IL-6 is recognized by IL-6R, which has an intracellular signaling akin to ObR for leptin, to stimulate gp130 and activate STAT3. Thus, IL-6 activates or potentiates the same intracellular anorexigenic signaling for leptin [247,248,249] (Figure 3).
• IL-6 slows gastric emptying to reduce postprandial glycaemia to negatively impact appetite and energy intake [250] (Figure 3). Generally speaking, the effects of signals of energy balance, such as leptin, GLP-1, and amylin, are modulated by the effects of IL-6 on hampering food intake and body weight [140,205,230,247] (Figure 3).

Growth differentiating factor 15 (GDF15) is another factor regulating energy balance. GDF15 is a member of the TGF-β superfamily and is expressed in several tissues, including the liver, kidney, intestines, and placenta, and is upregulated in response to various stresses/diseases, such as tissue injury, some cancers [pancreatic, prostate, and lung], obesity, heart failure infection, and mitochondrial diseases [251,252,253,254,255,256]. The expression of GDF15 mRNA in healthy mice is the highest in the kidney, followed by the liver, white and brown adipose tissues, and skeletal muscle [257,258]. Individuals with obesity and obese mice have increased circulatory levels of GDF15 compared with healthy controls [259,260,261] (Figure 1). The infiltration of circulating immune cells into the liver [262,263] activates downstream endoplasmic reticulum stress signaling proteins [including transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)] [258,264,265,266], which may upregulate GDF15 expression in obesity.

Increased tissue expression and circulation of GDF15 in obesity may be a compensatory mechanism in resisting obesity since treatment with recombinant GDF15 resulted in weight loss in mice that were fed a high-fat diet [252,267,268,269]. The inhibition of appetite and energy intake induced by exercise is also associated with increases in GDF15 in healthy individuals, individuals with obesity, and athletic individuals in duration- and intensity-dependent manners [270] (Figure 3). Aerobic exercise at 67% VO2max for 1 h in healthy individuals increased circulatory GDF15 levels [271], with similar findings also being reported following exercise with longer durations [272]. In this case, professional rugby players demonstrated elevated circulating GDF15 levels following a 12-week high-intensity training program [273], with comparable observations reported in healthy, lean individuals [274,275].

Increases in fasting GDF15 levels in individuals with obesity following 12 weeks of aerobic training on a treadmill/cycle ergometer (5 days/week, 60 min/session, at a 85% maximal heart rate) reduced fat mass [276]. Another report comparing changes in GDF15 after acute and chronic exercise [6-month moderate and vigorous exercise training] in individuals with overweight/obesity reported increases in circulatory GDF15 without other changes after exercise training [277]. In accordance with these findings related to increased GDF15 in adiposity, a study by Sabaratnam and colleagues measured increases in muscle expression and serum GDF15 levels immediately and 3 h after acute exercise (1 h at 70% VO2max) [278]. However, GDF15 levels are higher in sedentary individuals compared with active individuals [275].

Studies reporting that exercise lowers GDF15 levels in individuals with obesity [279] may also be related to lower body weights\ as there is an inverse relationship between resting plasma GDF15 levels and fitness [275,280], suggesting that exercise training can counteract increases in GDF15 levels. While some tissues, such as the skeletal muscle, heart, kidney, adipose tissue, prostate, and brain, increase GDF15 levels in response to exercise [257,258,272,274,281,282,283,284,285], the liver is the main source of its circulatory pool as the liver is energetically stressed during exercise [286,287]. Although the regulatory factors of GDF15 synthesis and release during exercise are not well understood, some mechanisms have been proposed. Exercise increases physiological and metabolic stress, particularly in the liver [288,289], to initiate ERS, which in turn activates the UPR and IRS pathways (IRE1α and PERK) in order to increase GDF15 transcription [281,290]. Exercise increases hepatic glucose production [291] and energetic stress [292,293,294], which in turn actuate hepatic AMPK activity to promote GDF15 levels [295]. Increased and decreased levels of circulating glucagon and insulin, respectively, after exercise directly promote Gdf15 gene transcription in the liver [290] (Figure 3).

Increases in GDF15 leads to weight loss by impacting appetite, food intake, and lipid metabolism [296,297,298], likely by actions on the CNS [299] and by binding to a high-affinity GDNF family receptor α-like (GFRAL) receptor, which is extensively expressed on cholecystokinin neurons located in the ARC, parabrachial nucleus (PBN), PVN, and area postrema (AP) in the hypothalamus [253,268,299,300,301,302] to regulate appetite and food intake. The binding of GDF15 to GFRAL leads to the formation of a complex with the co-receptor of proto-oncogene tyrosine-protein kinase Ret (RET), which then phosphorylates and activates the extracellular signal-regulated kinase (ERK), Akt, and phospholipase C-gamma (PLCγ) pathways in the CNS [268,300,301,302] to suppress appetite (Figure 3).

Changes in food preferences, taste aversion, and slowing of gastric emptying are other mechanisms by which GDF15 reduces food/energy intake and body weight [251,258,303]. The effects of GDF15 treatment on body weight in mice fed a high-fat diet are related to changes in food/taste preferences, especially with a reduced consumption of high-caloric/high-fat diets [269,304]. Loss of GDF15 activity in mice led to increases in body weight, while the pharmacological administration of GDF15 caused a taste aversion response [258]. GDF15-inducible taste aversion behaviors partly reduce appetite and food intake [258,303,305] and may be mediated by serotonin [306]. Additionally, treatment with GDF15 delays gastric emptying [269] that is mediated by afferent and efferent vagal signals that modulate postprandial gastric emptying [307]. Upon interaction with central GFRAL receptors, GDF15 reduces the activation of vagal nerves to slow gastric emptying [251,269,300,308] (Figure 3). The injection of GDF15-expressing tumors in mice reduced body weight and energy intake and was attributed to decreased and increased levels of hypothalamic NPY and POMC mRNAs, respectively, as well as downstream signaling by leptin, which upregulates STAT3 in hypothalamic neurons [163,296,309,310] (Figure 3). Thus, GDF15 impacts food intake and, consequently, body weight by modulating central neuropeptides and potentiating signaling by other appetite-regulating hormones.

Reduced food intake and appetite are not the only mechanisms by which GDF15 mediates the effects of exercise on body weight. A correlation was observed between the reduction in abdominal fat mass and the upregulation of GDF15 in inactive individuals with obesity after 12 weeks of treadmill/cycling aerobic training [276]. Long-term GDF15 administration and overexpression induce weight loss characterized by selective fat mass reduction without lean mass depletion [311,312,313]. Long-term increases in GDF15 levels are associated with secondary adaptations related to energy expenditure and the expression of thermogenic and lipolytic genes, such as increased expression in uncoupling protein 1 (UCP1) mRNA in adipose tissues [314,315], browning of white adipose tissue [316], and elevated expression of β-oxidative, thermogenesis, and lipolytic genes, such as adipose triglyceride lipase (Atgl), hormone-sensitive lipase (Hsl), and β-3 adrenergic receptor (Adrb3) [314,317]. Such increases in lipolytic genes in adipose tissue occurred in transgenic mice overexpressing GDF15 that resulted in reduced body fat [318]. These effects suggest that the GFRAL receptor may be expressed in adipose tissues so that GDF15 could exert its effects. The upregulation of Atgl gene expression by GDF15 in adipose tissue is abolished in GFRAL-deficient mice [319]. GFRAL receptors are extensively expressed in both subcutaneous and abdominal adipose tissues [301,317]. In summary, GDF15 reduces body weight by acting in the CNS to suppress appetite and energy intake and stimulates lipolysis in adipose tissues.

4. Exercise, BDNF and Appetite

Several other genes can also regulate obesity and food intake [320]. Satiety and increased energy expenditure are the two leading regulators of total energy balance that are mediated by BDNF, a member of the neurotrophin family [321] that is expressed in peripheral neurons and the CNS where it regulates synaptic activity, neurotransmission, and plasticity in mature neurons [322]. This trophic factor interacts with p75 neurotrophin receptor (p75 NTR) and tyrosine kinase B receptor (TrkB); pro-BDNF preferentially binds to P75 NTR and initiates apoptosis, while mature BDNF (mBDNF) binds to TrkB to trigger neural development and differentiation, cell survival, and synaptic plasticity. Binding BDNF to TrkB activates mitogen-activated protein kinase (MAPK), PLCγ, and phosphoinositide 3-kinas (PI3K) activity [323]. The expression of BDNF mRNA and protein is abundant in the CNS compared with other tissues during development [324], and both its mRNA and protein levels are extensively distributed in the hippocampus, amygdala, cerebellum, brain cortex, and hypothalamus in the adult brain [323]. The expression of BDNF and TrkB is often constrained to neurons [325], although they are also expressed in other non-neurogenic tissues, such as skeletal muscle [326], airway smooth muscle [327], and ovarian tissue [328]. Peripheral tissue-produced BDNF does not enter the circulation, while its central production can cross the BBB and is stored in peripheral tissue such as platelets [329].

The levels of BDNF mRNA in the brain, particularly in the hypothalamus, are highly dependent on nutritional status or energy availability. Thus, fasting and food restriction mitigate BDNF mRNA levels in various parts of the hypothalamus [330,331,332] and are elevated after refeeding [333]. These studies suggest an important role for BDNF in controlling body weight and energy homeostasis that is beyond neurological plasticity. There is a bidirectional negative correlation between BDNF and obesity, where low circulatory levels of BDNF are associated with severe obesity, hyperphagia [334], and adiposity [335] (Figure 1). Several endogenous and exogenous factors, such as stress, exercise, brain damage, and diet, regulate BDNF gene expression [336]. Obesity increases circulatory cortisol (in humans) or corticosterone (in rodents) [337,338], pro-inflammatory cytokines [339,340], and oxidative stress [341] to reduce peripheral and central BDNF mRNA and protein levels.

The effects of physical activity on increasing circulatory BDNF levels are dependent on exercise duration and its intensity; thus, acute and chronic high-intensity exercises (>85% maximum heart rate or >80% VO2max) increased BDNF levels in males with obesity [342,343,344,345], with similar findings being observed in women with obesity after moderate-intensity resistance training (55–65% 1RM) [346]. In addition, high- and moderate-intensity aerobic training in healthy individuals [297] and those with obesity [298] for 12 weeks raised the resting serum levels of BDNF. Exercise in an animal model upregulates the expression levels of hippocampal BDNF and its TrkB receptor [347,348]. Exercise not only changes the expression of BDNF and its receptor in the hippocampus, but it also does so in the hypothalamus; it was observed that 4 weeks of running promoted BDNF expression in the hypothalamic ARC [349,350,351].

Exercise increases BDNF levels by several mechanisms, including elevated neuronal activity, improved cerebral blood flow and energetic stress, and the release of humoral molecules such as adipokines, myokines, and hepatokines. Exercise stimulates the release glutamate, which then interacts with its postsynaptic receptors (AMPA and NMDA) to facilitate the influx of Na⁺ and Ca²⁺ via ligand and voltage-gated Ca²⁺ channels into neural cells. Elevated intracellular Ca²⁺ activates transcription factors (CaRF), including CaRF 1 and CaRF3, PKC, CaMK, and MAPK, which in turn activate/phosphorylate the transcription factors of CREB, NF-κB, and AP-1 to increase central and peripheral BDNF mRNA and protein levels [352,353,354,355,356,357] (Figure 4). Increased synaptic activation by exercise-induced shear stress is accompanied with increased blood flow in sensory–motor regions involved in cognitive capacity [358,359,360]. Central and peripheral endothelial cells are the most active in BDNF synthesis, secretion, and its regulation [361,362]. Increased vascular shear stress stimulates the production, influx, and activation of tissue plasminogen activator (tPA) from endothelial cells. Circulating tissue plasminogen activator (tPA), derived from skeletal muscle endothelial cells, crosses the blood-brain barrier (BBB) via low-density lipoprotein receptor-related protein (LRP)-mediated transport. Central endothelial cell-derived tPA enhances brain-derived neurotrophic factor (BDNF) expression through two distinct mechanisms: (1) direct cleavage of pro-BDNF to mature BDNF, and (2) facilitation of neuronal NMDA receptor activation, which stimulates Ca²⁺ influx and subsequent BDNF upregulation [363,364,365,366].

Shear stress activates endothelial nitric oxide synthase (eNOS) and the production of endothelial NO, leading to increased BDNF expression [358] (Figure 4). As with skeletal muscles during exercise, the activation of excitatory synapses and neuronal action potentials to restore transmembrane ionic gradients requires ATP, leading to energetic stress in the brain [352,367,368]. Energetic stress increases ROS production by neurons and leads to the expression of transcription regulating factors such as cAMP response element-binding protein (CREB), nuclear factor-kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), hypoxia-inducible factor 1α (HIF-1α), and peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), leading to increased BDNF expression [369,370,371] (Figure 4). Additionally, increased energy demand elevates the AMP/ATP ratio and activates the AMPK pathway, causing increases in nicotinamide adenine dinucleotide (NADH+) to activate sirtuin 1 (SIRT1) factor and the transcription factor of methyl CpG binding protein 2 (MeCP2), which increase BDNF expression by activating CREB [372]. Activated SIRT1 in the brain can also downregulate miRNA-134 levels, which inhibits CREB translation and increases BDNF expression [373] (Figure 4).

Skeletal muscle releases myokines in response to exercise to change the expression of local genes or genes in other organs [199]. High-intensity exercise increases the production of lactate that is released into the circulation and enters the brain via MCTs to activate GPRs and SIRT1, which then stimulate the expression and activation of proteins involved in mitochondrial biogenesis, including PGC-1α, ERRα, and FNDC5/irisin. Elevated PGC-1α levels in both skeletal muscle and the brain increase FNDC5 expression, which then undergoes proteolytic cleavage to produce irisin. Peripheral irisin produced by muscle crosses the BBB to activate the cAMP/PKC//CREB pathway to upregulate central BDNF by binding to integrin αvβ5 receptors on cerebral endothelial cells [374,375,376,377,378] (Figure 4). Elevated levels of lactate following high-intensity exercise also activates CREB to increase BDNF levels by stimulating neuronal glutamatergic transmission and activating NMDA receptor signaling [379,380]. Vigorous levels of exercise increase hydrogen peroxide (H₂O₂) and TNF-α levels to activate PGC-1α signaling that promotes central BDNF synthesis [381]. The central and peripheral activation of PGC-1α stimulates kynurenine aminotransferase (KAT), which converts kynurenine to kynurenic acid to increase the plasma levels of kynurenic acid and the upregulation of central BDNF expression [382] (Figure 4). IL-6 is another myokine released into the circulation in response to exercise and influences osteocytes to liberate non-carboxylated osteocalcin, which binds to the orphan type of the GPR receptor (Gpr158) in the brain to boost the production of IP3 in neurons and stimulate the production of BDNF in a Ca²⁺-dependent manner [383,384,385] (Figure 4). Exercising muscle also expresses cathepsin-B (CAT-B) mRNA and protein to increase cerebral BDNF levels [386] (Figure 4).

Exercise-induced release of hepatokines, such as insulin-like growth factor 1 (IGF-1), β-hydroxybutyrate (BHB), fibroblast growth factor 21 (FGF21), and glycosylphosphatidylinositol specific phospholipase D1 (GPLD1), is another mechanism by which central BDNF levels are increased [349,387,388,389,390,391]. For instance, circulatory BHB crosses the BBB and then binds to histone deacetylase 2/3 (HDAC2/3) to inhibit their inhibitory function on the BDNF gene promotor [349] (Figure 4). Additionally, exercise releases FGF21 from hepatocytes due to increases in the glucagon-to-insulin ratio and enters the brain to activate the AMPK pathway, leading to an increase in central BDNF levels [388,391,392,393,394] (Figure 4). Platelets are a rich source of circulatory BDNF that is secreted following exercise-induced thrombocytosis [326,395] that ceases 15–30 min after exercise [396] (Figure 4). Exercise stimulates epithelial gut cells to produce and release GLP-1 into the circulation, which then enters the brain to bind to its neural receptors that are coupled with cAMP production to activate CREB and increase BDNF expression [122,397] (Figure 4).

Epigenetic modulations represent another mechanism through which exercise affects central and peripheral BDNF expression. Exercise influences the activation of enzymes responsible for DNA methylation (DNMT), histone acetylation (HAT), or histone deacetylase (HDAC) on BDNF promotors to increase BDNF transcription [349,398] (Figure 4). In this context, HDAC inhibition is followed by the increased expression of muscle BDNF levels after exercise [399,400]. In addition, exercise removes the inhibition of trimethylated histone H3 at lysine 4 (H3K4me3) on the BDNF promotor gene, leading to increased BDNF expression [401]. Elevated DNA demethylation on promotor areas of BDNF is another pathway by which exercise overshadows BDNF expression in favor of its expression [398] (Figure 4). High levels of glucose curb the output of BDNF by the brain [402,403]. Increases in neurotransmitter release during exercise, such as acetylcholine, norepinephrine, dopamine, and serotonin, promote BDNF expression [404,405,406,407,408,409] (Figure 4). Exercise upregulates leptin expression in the brain and other tissues [410,411] to produce the melanocortin precursor of α-melanocyte-stimulating hormone (α-MSH) by binding to LEPR. Increases in α-MSH leads to the upregulation of melanocortin 4 receptors (MC4R) that promote cerebral BDNF expression [412,413] (Figure 4).

BDNF is a leading component of the hypothalamic pathway controlling body weight and energy homeostasis in addition to its role in metabolism through increasing fat oxidation in muscle [326,414,415,416]. BDNF and its receptors are mostly expressed in various hypothalamic nuclei and other brain areas related to monitoring energy balance, including the ventromedial nucleus of the hypothalamus (VMH), paraventricular hypothalamic nucleus (PVH), nucleus accumbens, nucleus tractus solitarius (NTS), ventral tegmental area (VTA), and ARC [enriched in TrkB without the expression of BDNF] [330,417,418,419,420,421,422,423]. Although the ARC does not synthesize BDNF synthesis, TrkB receptors and nervous fibers containing BDNF in this area suggest a role in influencing food intake [420]. These interactive central hubs integrate acute satiety, hunger signs, and chronic obese signals from periphery in response to food intake [424]. Preclinical document using chronic intracerebroventricular BDNF administration in rats established its anorexigenic effects through body weight modulation, confirming BDNF’s appetite-regulatory function [425]. Later investigations bolstered the role of BDNF in energy balance in modified genetic animals in which BDNF has been deleted. In this context, it has been disclosed that BDNF+/- mice with reduced hypothalamic BDNF expression exhibit hyperphagia and develop an obese phenotype, both of which are reversible upon BDNF infusion [418,426,427,428]. There are many studies in animals and humans indicating that the genetic deletion/mutation of BDNF or its receptor in brain areas related to appetite leads to obesity and hyperphagia [332,418,428,429,430,431,432]. Acute and chronic intracerebral injections of BDNF suppresses food intake and boosts metabolic rate, resulting in a loss of body weight [333,416,423,433,434,435,436]. Similar findings of reduced energy intake were also shown after the peripheral and subcutaneous injection of BDNF in animal models of obesity caused by high-fat diets [402,436,437,438,439]. Thus, central BDNF mitigates food intake (appetite suppression and hypophagia) through central mechanisms and increasing energy expenditure by elevating heat production, resting metabolism, and the respiratory exchange ratio (RER) to promote body weight loss and fat mass reduction in adiposity.

BDNF regulates energy balance by either directly activating its receptors in hypothalamic neurons monitoring food intake or indirectly by intensifying or hindering other endocrine hormones contributing to appetite regulation [414,439,440,441]. Changes in synaptic connectivity and neural activation in hypothalamic circuits primarily contributes to appetite control and feeding behavior [442]. BDNF activates MAPK, PI3K, and PLC after interacting with its receptor in the hypothalamus. These activated signals regulate synaptic maintenance and plasticity, synaptogenesis, neurite growth, and neural survive, which are key in forming neural circuits throughout the brain, including those regulating energy homeostasis and appetite [321,355,443,444,445,446,447] (Figure 5). Thus, BDNF increases the expression level of thrombospondin (TSP) receptors to promote the function of excitatory synapses [442], followed by alterations in behaviors related to food intake [446] (Figure 5). Additionally, BDNF is required for the growth and transmission of serotonergic fibers to reduce appetite and obesity, as BDNF deletion reduces serotonin levels and increases adiposity [426,448,449,450] (Figure 5). Other studies report that the intracerebroventricular injection of BDNF in rats increased the hypothalamic 5-Hydroxyindoleacetic acid/5-hydroxytriptamine (5-HIAA/5-HT) ratio and increased 5-HT turnover to hinder feeding and suppress appetite [426,434,450,451] (Figure 5). BDNF modulates the expression of hypothalamic orexigenic and anorexigenic genes, such as thyrotropin-releasing hormone (TRH), TrkB, POMC, LEPR, corticotropin-releasing hormone (CRH), and urocortin (UCN) [440,441,452,453]. Hypothalamic TrkB is localized to CRH and increases BDNF in the hypothalamus, either by external administration or by exercise, and upregulates CRH and UCN mRNA [351,433,454]. CRH is a stress response hormone, and UCN is a member of the CRH peptide family, and after binding to their receptors (CRH-R1 and CRH-R2), they activate the adenylate cyclase-PKA, PLC-PKC, and ERK-MAPK pathways to suppress food intake and appetite (Figure 5) and increase energy expenditure by augmenting SNS function [455,456,457,458,459]. The inhibition of both CRH-R1 and CHR-R2 in the hypothalamus with anti-SG30 reduces the anorexigenic and anti-obese effects of BDNF [433]. Increased CRH mRNA in PVN neurons, which is extruded into the locus coeruleus and rostral medial medulla, where sympathetic neurons are activated, is associated with increases in epinephrine and norepinephrine as well as increased oxygen consumption [460,461,462]. These catecholamines then activate β-adrenergic receptors in adipose tissue to increase thermogenesis by upregulating UCP-1, leading to a reduction in body weight [463,464]. There is a close interaction of CRH neurons and NPY neurons in the hypothalamus that results in a neuroanatomical circuit that downregulates NPY [465] (Figure 5). In addition to generating anorexigenic signals, BDNF also inhibits orexigenic pathways [423]. The paraventricular nucleus (PVN) sends efferent projections to neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC). These ARC neurons subsequently release appetite-modulating peptides [466]. Increased expression of BDNF in hypothalamic areas can interfere with NPYergic pathways to downregulate and normalize hypothalamic NPY expression, followed by suppressing NPY-mediated feeding or its orexigenic pathways [423,467] (Figure 5). The NPY that is secreted inhibits TRH neurons in the hypothalamus [468]. In contrast, BDNF upregulates hypothalamic TRH expression after binding to TrkB receptors on TRH neurons to exert part of its actions to reduce appetite and food intake [441,453,469]. TRH neurons in the hypothalamus, especially in the PVN, project Raph pallidus (RPα) neurons in the hindbrain, after which preganglionic sympathetic neurons in the spinal cord activate thermogenesis in skeletal muscle and adipose tissues [416,468,470]. Increases in thermogenesis due to sympathetic activation increase energy expenditure in part due to the upregulation of UCP-1, leading to increased energy expenditure [416,435,471]. Additionally, TRH neurons also increase the thermogenic effects of norepinephrine in both skeletal muscle and adipose tissue by releasing thyroid-stimulating hormone (TSH) from the pituitary gland [472,473].

BDNF suppresses appetite by promoting the function of alpha2/delta 1 (α2δ-1) (Figure 5), a hypothalamic protein involved in feeding behaviors and the function of BDNF in appetite-regulating pathways. The inhibition of this protein in normal mice increased food intake and weight gain, while reducing BDNF levels diminished hypothalamic function [442]. Increases in α2δ-1 protein increase the appetite-hindering function of BDNF by several mechanisms, including increasing synaptic connectivity in hypothalamus via interactions with TSPs, increasing the density and force of excitatory synapses of anorexigenic neurons by excitatory synaptogenesis, facilitating the trafficking of voltage-gated calcium channels on cells associated with neurotransmitter release, and boosting synaptogenesis in a Ca²⁺-independent manner [474,475,476] (Figure 5).

The complex behavior of food intake is not only coordinated by homeostatic mechanisms in the brain but is also regulated via hedonic factors involving the mesolimbic dopamine reward pathway (MDP) [446,477]. MDP regulates motivated and reward-seeking behaviors and contains dopamine neurons in the VTA, which intrude into the nucleus accumbens and medial prefrontal cortex. This neural circuit coordinates the behavioral effects of drug abuse and rewards such as food and initiates synaptic dopamine transmission in mesolimbic targets [477,478,479,480,481]. BDNF and its receptors are expressed in the MDP and nucleus accumbens (an area with relatively low endogenous BDNF expression), where they regulate hedonic feeding [482,483,484] (Figure 5). Increased BDNF levels in the VTA (mesolimbic pathway) of mice with high-fat-diet-induced obesity lowered the intake of food with a high fat content and reduced adiposity in these animals. Central deletion of BDNF has similar effects to failed dopamine transmission due to high-fat diets [481]. In essence, BDNF modulates the excitability of dopaminergic neurons in the VTA and potentiates dopamine binding to its receptor (D1R), which it in turn reduces hyperphagic behaviors and appetite and dampens responses to food reward [481,485] (Figure 5). Intensifying the signaling pathways of other anorexigenic factors, such as leptin and α-MSH, in the hypothalamus is another mechanism through which BDNF can suppress appetite [330,402,417,433,436,440,486]. These anorexic effects induced by BDNF are mediated, in part, by upregulating their receptors (LEPR and MC4R), as well as by increasing the release of POMC and α-MSH hypothalamic POMC neurons [330,453,454] (Figure 5).

5. Exercise and Eating Behaviors

Exercise indirectly regulates appetite by mitigating the neural response in areas of the brain involved with visual process, attention, and motivation [487], as shown in a study where cycling for 1 h (at 83% of maximum heart rate) reduced neuronal responses to pictures of food [488]. Eating behaviors in humans are not only determined by hunger, satiety, and energy stores but also by complex factors such as sensory stimuli, attention, emotion, and some cognitive aspects [489]. The insular cortex (a distinct lobe of the cerebral cortex) is important in determining human behaviors related to cognitive function [490,491], and individuals motivated to eat have a constant neural response in the insular cortex [492,493]. Thus, the neural response to visual cues of food is diminished in this cortex by a single bout/constant exercise (Figure 6). Prefrontal and orbitofrontal cortices, the hippocampus, and the visual cortex are brain regions responding to reward with roles in reducing or increasing appetite and eating motivation (Figure 6). Exercise reduces the activity of these brain regions, as shown by an fMRI analysis [487,488,493,494,495]. Details of the mechanisms by which both acute and chronic exercise impact the response of the brain’s reward systems to food cues require further investigation. However, it is likely that body movements cause dynamic changes in hemodynamic and metabolic regulation, myokine release, and muscle inflammation to influence cognitive and emotional brain circuits regulating appetite and eating motivation.

6. Exercise and Gastric Motility and Emptying

Exercise also modulates gastric motility associated with gastric emptying and has been suggested as a rate-limiting step in the transfer of nutritional substances to the small intestine to temporarily inhibit appetite and the desire to eat [496,497] (Figure 6). Food entering the small intestine causes gastric distention, the stimulation of intestinal mechano- and chemo-receptors, and the release of several gut peptides [498,499]. The influence of gastric distention on appetite is mediated by stimulating stretch and tension mechanoreceptors, which then signal the brain [500,501]. Researches have established a direct relationship between satiety perception and gastric distension [502,503] and an inverse correlation between gastric volume and food intake [504]. Hence, an accelerated rate of gastric emptying abates gastric distention associated with overeating, while slower gastric emptying is associated with gastric distention, the feeling of fullness, and reduced food intake [503,505]. Additionally, a delay in gastric emptying into the small intestine is commensurate with mitigating the effects of intestinal appetite peptides [506]. Exercise improves gastrointestinal function, including the gastric emptying rate and gut motility [507,508,509]. Chronic exercise-mediated faster emptying is accompanied with an increased desire to consume food [508] and increased meal frequency by reduced gastric distention and fullness, which are compensatory mechanisms to meet expenditure energy during exercise [510]. These effects on the gastrointestinal tract are dependent on exercise intensity and duration, the food volume, and the amount of food consumed before exercise [511,512,513,514]. In this context, it has been indicated that faster gastric emptying, as an adaptation to exercise training, only emerges in individuals who have trained for a long period of time, at least 6 months [509]. Consistently, a 4-week exercise protocol that combined high-intensity and continuous exercise failed to increase gastric emptying in men with overweight/obesity [515]. According to precedent reports, the intensity of exercise has an important role in gastric motility, or rather, the gastric emptying rate, such that it is accelerated during low-intensity exercises and delayed during high-intensity exercises [516,517]. Low-intensity exercise accelerates gastric emptying (characterized by expelling looser stool) compared to moderate or high-intensity exercise [516]. Diminished gastric motility mediated by high-intensity exercise reduces appetite [37,517], partly due to increased lactate concentrations and sympathetic stimulation during these exercise types (Figure 6). An increased lactate concentration promotes CO₂ production to cause the bicarbonate-mediated buffering of H+ ions [518]; CO₂ incurs intestine distention and alters gastric motility [519].

In addition to the enteric nervous system controlling the gastrointestinal function, the extrinsic innervation of the gastrointestinal tract by sympathetic and parasympathetic nerves also regulates, modulates, and coordinates gastrointestinal function [520]. The sympathetic innervation of the gastrointestinal tract originates from the intermediolateral column of the thoracolumbar spinal cord [521] and provides an inhibitory input to the smooth muscle of the gastrointestinal tract, resulting in tonic inhibitory effects on mucosal secretion and reduced gastrointestinal blood flow by causing vasoconstriction. The modulation of gastrointestinal motility primarily occurs by the modulation of the presynaptic release of neurotransmitters. However, parasympathetic nerves also provide both inhibitory and excitatory inputs to the stomach and small intestine, allowing for the precise control of gastrointestinal function. Extrinsic parasympathetic inputs to the stomach and gastrointestinal tract are supplied by the vagus nerve and efferent cell bodies, which are located in the dorsal motor nucleus (DMV) in the hindbrain [522,523,524]. Neurons of the DMV regulate gastric function [525,526] in addition to synaptic inputs from adjacent nucleus tractus solitarius that control the function of these neurons. Accordingly, excitatory catecholaminergic and glutamatergic inputs and inhibitory GABAergic regulate the function/excitation of DMV neurons [526,527,528,529]. The modulation of GABAergic synaptic inputs can potentially affect excitatory DMV and the vagal efferent control of gastric motility. Stress is a status of homeostatic derangement resulting from external and internal factors and is encountered by a bevy of automatic responses and behaviors to restore homeostasis.

Acute and chronic exercises, as brief and long stressors, are challenges for the sustained engagement of autonomic neurocircuits and behaviors to restore body homeostasis. Upon the initiation of exercise, the autonomic nervous system, particularly the sympathetic system, is activated depending on the type and intensity of exercise and is reduced by repeated exercise training, as an adaptation mechanism, followed by regulation by the parasympathetic system [530,531,532]. Increased sympathetic input mediated by acute exercise temporarily affects gastrointestinal function, mitigates gastric emptying, and increases colonic motility [533,534,535,536] (Figure 6). Diminished gastric emptying is associated with a sensation of fullness that reduces appetite. In addition to improved autonomic balance in favor of parasympathetic dominance, exercise training is also accompanied with the upregulation of oxytocin and catecholamine regulation of the DVC to restore gastrointestinal function [537,538].

7. Exercise, Mental Stress, and Appetite

Reducing mental stress is another mechanism through which exercise can suppress appetite (Figure 6). Mental stress is associated with the hyperactivation of both the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis (HPA), which in turn increases the production of catecholamines and cortisol [539,540]. Cortisol causes hyperinsulinemia [541,542] by inhibiting glucose transporter type 4 (GLUT4) recruitment to the cell membrane and reducing IRS-1 levels [543]. Hyperinsulinemia increases body fat mass by inhibiting fatty acid oxidation, and hypercortisolemia also leads to leptin resistance and increased NPY levels [544,545,546]. Insulin, cortisol, and NPY are critical instigators of appetite and increased food consumption [547,548,549]. Increased food intake reduces stress by impacting the corticolimbic area of the brain, a region related to sensing pleasure and stress [550,551]. There is an inverse correlation between exercise and stress levels [552]. A high level of physical fitness reduces psychological stressors [539,553] and attenuates sympathetic responses to stress [554] (Figure 6). Lower depressive states and reduced rates of urine cortisol (as a parameter of HPA activity) and lower epinephrine levels (as an indicator of sympathetic system activity) occur after 8 of weeks regular exercise in females with mild to moderate depression [555]. Activation of the HPA causes cortisol release by the pituitary gland, which secretes adrenocorticotropic hormones, which in turn stimulate cortisol secretion from the adrenal cortex. Lower cortisol concentrations after chronic exercise may partly refer to the attenuated rate of perceived exertion for performing a given exercise [556]. In addition, the increased secretion of neurotransmitters such as serotonin and dopamine after exercise training triggers the secretion of endorphins, which are associated with euphoria and may lower psychological stress [557,558] (Figure 6). In summary, reduced levels of stress hormones and increases in pleasure hormones following exercise are associated with reduced psychological stress, which in turn suppresses appetite.

8. Exercise, Body Temperature, and Appetite

Alterations in body temperature can also affect appetite [488], but the molecular mechanisms underlying this phenomenon are not fully understood (Figure 6). The hypothalamus contains thermosensitive neurons that respond to changes in temperature. Elevated body temperature activates these neurons, triggering the release of anorexigenic neurochemicals, including α-MSH (derived from POMC), serotonin, dopamine, collectively contribute to reduced food intake and appetite suppression [559,560,561,562]. Exercise increases the volume and activation of brown adipose tissue (BAT), a type of fat tissue that generates heat due to the activation of β-adrenergic receptors. Increased body temperature triggered by BAT activation leads reduced serum ghrelin concentrations that can suppress appetite [563,564,565,566,567] (Figure 6). The specific mechanisms by which body temperature affects hormone secretion and signaling are unclear, but recent studies indicate that the BAT-stimulated regulation of food intake is related to secretin, a satiety hormone [568,569]. Secretin binds to its receptors on BAT and activates BAT thermogenesis to then activate POMC neurons in the medio-basal hypothalamus by afferent sensory neurons innervating BAT [569,570,571,572], leading to quenching brain reward-related responses to food cues [573,574] (Figure 6).

The core body temperature is increased after exposure to a high-temperature environment, prolonged exercise, and in pathological conditions such as febrile diseases. These conditions can suppress appetite instantly, after several hours, or days after exposure. The activation of POMC neurons in response to warm temperatures is mediated by temperature-sensitive cation channels of transient receptor potential vanilloid 1 (TRPV1) [575] (Figure 6). TRPV1 channels belong to the transient receptor potential (TRP) cation channel family and consist of four subunits (TRPV1-4). These channels transduce information on core body and ambient temperatures to the ARC region of the hypothalamus that controls the core body temperature. Both TRPV1 and TRPV2 ion channels transduce noxious temperatures such that TRPV1 channels are sensitive to temperatures of up to 42 °C [575] and TRPV2 channels are sensitive to temperatures higher than 52 °C [576]. Additionally, the sensitivity of the TRPV3 and TRPV4 channels are in the innocuous ranges of 32–39 °C [577] and 27–35 °C [578], respectively. These channels can form functional heteromeric channels with other channel subunits. For example, TRPV1/TRPV3, TRPV1/TRPV4, and TRPV3/TRPV4 are functional TRPV1-like receptors expressed on POMC neurons that are activated at physiological temperature levels [579]. Exercise performed by mice (40 min running on a treadmill) increased the ARC temperature to 38–39 °C and reduced food intake for 1 h compared with mice that did not exercise; the suppressing effects of exercise on appetite were reduced when the Trpv1 gene in POMC neurons was deleted [580]. POMC neurons express functional TRPV1-like receptors, which increase the activation of these neurons as the core and brain temperatures are increased and lead to appetite suppression after exercise [570]. It has been suggested that chronic stimulation of ARC POMC neurons is essential to mitigate food intake [581,582]. Therefore, investigations of appetite suppression mediated by thermogenic factors should distinguish between acute and chronic stimulation paradigms.

9. Conclusions

Exercise may restore the effects of obesity on factors regulating appetite and food intake. Exercise modulates the actions of ghrelin and leptin and promotes the secretion of adiponectin, GLP-1, CCK, and PYY. Exercise-induced elevation of metabolic factors (lactate, IL-6, GDF15, BDNF) represents an additional mechanism for appetite suppression. Exercise also lowers appetite by altering responses to visual food cues and reward areas, gastric emptying, and mental stress. Additionally, exercise increases the volume and activation of brown adipose tissue to elevate the core body temperature, which leads to reductions in appetite.

10. Future Direction

Appetite regulation is a complicated process to which various factors contribute. To our knowledge, appetite investigations—especially in individuals with obesity —are still in their early stages and require the consideration of multiple factors and a conclusive standpoint when evaluating changes following internal or external agents. The responses of appetite to acute and chronic exercise are partly different, which may be attributed to the divergent responses of various appetite-regulating hormones. Therefore, it would be better if the response of each appetite-regulating hormone was clearly elucidated. Appetite exhibits distinct responses in healthy non-athletic individuals, healthy athletic individuals, and individuals with obesity following exercise and exercise training. Thus, examining how appetite is modified in these populations in response to various exercise interventions is highly meritorious.

Some metabolites, such as the lactate-to-phenylalanine (Lac/Phe) ratio, and factors like body temperature have profound effects on appetite, yet their precise mechanisms have not been fully elucidated. With this in mind, it is worthwhile to explore their changes during and after prolonged or intense exercise in individuals with obesity and to uncover the precise mechanisms influencing appetite. It is expected that future studies will investigate the combined effects of dietary interventions and exercise on appetite responses, not only in individuals with obesity but also in healthy and athletic populations.