# Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
## 2 Exercise and Appetite-Regulatory Hormones
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% VO2 max 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, CCK and CCK [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.