The Stomach in Health and Disease
The Stomach in Health and Disease
The vagus nerve innervates regions of the GI tract involved in calorie intake, satiation and digestion, and it serves as a crucial link between the brain, brainstem and gut. The afferent fibres of the ventral and dorsal vagal trunks in the abdomen are involved in mediating satiation and, as a result, regulating appetite. Vagal afferents are stimulated by change in viscus tension induced by food passing through the GI tract. The vagus nerve is also stimulated by hormonal mediators activated by mechanical and chemical stimuli. In the stomach, ghrelin secretion inhibits afferent vagal fibres to increase appetite (orexigenic), whereas leptin secreted in the stomach stimulates vagal fibres and induces satiety – an anorexigenic effect. Other anorexigenic hormones, such as CCK, GLP-1 or PYY, are released in the small intestine.
Efferent vagal neuronal fibres control much of the GI motor and secretory functions involved in food digestion and absorption. Partial vagotomy, or total sub-diaphragmatic vagotomy, or intermittent vagal nerve electrical stimulation performed to inhibit vagal function in humans decreased food intake and induced early satiety and weight loss. The vagus nerve plays a dual role, interacting with anorexigenic and orexigenic pathways that are altered in obesity and may contribute to body weight and glycaemic control.
The roles of the proximal stomach and ghrelin in appetite control are also illustrated by the effects of bariatric procedures. Thus, isolation of the gastric cardia/fundus and exclusion of the distal stomach from ingested food after Roux-Y gastric bypass may initially limit caloric intake by induction of nausea (and rarely vomiting), thereby discouraging overeating. In addition, stimulation of the gastric mechanical and chemical receptors, rapid emptying of the remaining stomach and release of ghrelin may also contribute to the induction of weight loss.
Ghrelin (see section 'Gastric hormones') is the most relevant gastric hormone involved in appetite. It is produced from the pre-pro ghrelin gene and undergoes cyclical changes in blood concentrations during fasting and postprandially, reaching highest levels during fasting. Acyl-ghrelin (AG) is metabolised by the ghrelin activating enzyme, ghrelin-O-acyltransferase, to deacyl-ghrelin (DAG). AG and DAG have different physiological effects: AG increases gastric emptying and appetite, whereas DAG decreases gastric emptying, induces postprandial fullness and improves insulin sensitivity.
In the vast majority of affected individuals, obesity involves overconsumption of food relative to calorie requirements. The control of appetite is partly determined by hedonic mechanisms, where food consumption affects brain systems associated with pleasure and reward, such as dopaminergic D2 and opioidergic mechanisms in areas such as the ventral tegmental area and the nucleus accumbens. The second homeostatic mechanisms are centred in the arcuate and paraventricular nucleus of the hypothalamus. Until recently, the focus of medical and behavioural therapy was directed to these central mechanisms including the recently launched medications such as bupropion-naltrexone, phentermine-topiramate, lorcaserin or the GLP-1 receptor agonist, liraglutide. However, these treatment approaches result in an average weight loss of ≤5 kg in clinical trials. The greater effectiveness of bariatric surgery, particularly Roux-en-Y gastric bypass, and sleeve gastrectomy clearly suggests that the stomach may play an important role in the control of appetite and food intake.
The sensory function of the stomach is, in part, determined by its motor functions such as tone and compliance, and by the rate of emptying. However, studies of gastric emptying in normal weight and obese persons have shown inconsistent results (reviewed in ref. 79). Gastric capacity was larger in obese persons when tested with an intragastric latex balloon filled with water. In contrast, other studies using the barostat or imaging (single-photon emission CT) techniques reported no differences in gastric volume or compliance between non-bulimic obese and lean subjects (reviewed in ref. 79). Recent studies from >500 patients ranging from normal body mass index (BMI) to class III obesity showed that gastric emptying of solids is faster and fasting gastric volume larger in obesity, confirming results in a prior, smaller study. In addition, other alterations in quantitative GI and behavioural traits associated with obesity were reduced satiation and satiety, altered body image, disorders of affect and reduced exercise. Principal component analysis identified latent dimensions that accounted for approximately 81% of the variation among overweight and obese subjects, including satiety or satiation (21%), gastric motility (14%), psychological factors (13%) and gastric sensorimotor factors (11%).
Increased body mass and fasting gastric volumes are independently associated with delayed satiation under standard laboratory conditions of food ingestion. Thus, Delgado-Aros and colleagues showed that, across a broad spectrum of BMI, there was an association between higher BMI, higher fasting gastric volume and decreased satiation (figure 4), manifested as reduced symptoms of fullness and a higher maximum tolerated volume of a nutrient drink ingested at a constant rate in a laboratory setting.
(Enlarge Image)
Figure 4.
Caloric intake at maximum satiation by gender and body mass index. There was higher caloric intake at maximum satiation in male subjects compared with women (left). Reproduced from ref. 82.
Figure 4 shows the higher maximum tolerated volume in obese compared with normal or underweight participants; an increase of 50 mL in the fasting gastric volume was associated with 114±32 kcal (479±134 kJ) more ingested at maximum satiation. These findings suggest that individuals with a higher BMI require more food to reach satiation (and, by inference, to signal termination of meal ingestion), and, over time, this results in higher caloric intake and weight gain (figure 4).
Other data support the importance of behavioural adaptation; thus, obese individuals have more severe symptoms of fullness, bloating, nausea and pain when reaching maximal satiation than individuals without obesity, and yet they continue to ingest calories, consistent with a behavioural adaptation to satiation. The additional understanding of the role of the stomach in obesity ushers in a new era when new medications, devices (such as balloons and drains or internal liners) and endoscopic interventions may prove more efficacious than the drugs targeting central mechanisms by targeting the GI functions that are critical for appetite and food intake.
The Stomach in Appetite Control and Obesity
Control of Appetite
The vagus nerve innervates regions of the GI tract involved in calorie intake, satiation and digestion, and it serves as a crucial link between the brain, brainstem and gut. The afferent fibres of the ventral and dorsal vagal trunks in the abdomen are involved in mediating satiation and, as a result, regulating appetite. Vagal afferents are stimulated by change in viscus tension induced by food passing through the GI tract. The vagus nerve is also stimulated by hormonal mediators activated by mechanical and chemical stimuli. In the stomach, ghrelin secretion inhibits afferent vagal fibres to increase appetite (orexigenic), whereas leptin secreted in the stomach stimulates vagal fibres and induces satiety – an anorexigenic effect. Other anorexigenic hormones, such as CCK, GLP-1 or PYY, are released in the small intestine.
Efferent vagal neuronal fibres control much of the GI motor and secretory functions involved in food digestion and absorption. Partial vagotomy, or total sub-diaphragmatic vagotomy, or intermittent vagal nerve electrical stimulation performed to inhibit vagal function in humans decreased food intake and induced early satiety and weight loss. The vagus nerve plays a dual role, interacting with anorexigenic and orexigenic pathways that are altered in obesity and may contribute to body weight and glycaemic control.
The roles of the proximal stomach and ghrelin in appetite control are also illustrated by the effects of bariatric procedures. Thus, isolation of the gastric cardia/fundus and exclusion of the distal stomach from ingested food after Roux-Y gastric bypass may initially limit caloric intake by induction of nausea (and rarely vomiting), thereby discouraging overeating. In addition, stimulation of the gastric mechanical and chemical receptors, rapid emptying of the remaining stomach and release of ghrelin may also contribute to the induction of weight loss.
Ghrelin (see section 'Gastric hormones') is the most relevant gastric hormone involved in appetite. It is produced from the pre-pro ghrelin gene and undergoes cyclical changes in blood concentrations during fasting and postprandially, reaching highest levels during fasting. Acyl-ghrelin (AG) is metabolised by the ghrelin activating enzyme, ghrelin-O-acyltransferase, to deacyl-ghrelin (DAG). AG and DAG have different physiological effects: AG increases gastric emptying and appetite, whereas DAG decreases gastric emptying, induces postprandial fullness and improves insulin sensitivity.
Gastric Motility, Sensation and Satiation in Obesity
In the vast majority of affected individuals, obesity involves overconsumption of food relative to calorie requirements. The control of appetite is partly determined by hedonic mechanisms, where food consumption affects brain systems associated with pleasure and reward, such as dopaminergic D2 and opioidergic mechanisms in areas such as the ventral tegmental area and the nucleus accumbens. The second homeostatic mechanisms are centred in the arcuate and paraventricular nucleus of the hypothalamus. Until recently, the focus of medical and behavioural therapy was directed to these central mechanisms including the recently launched medications such as bupropion-naltrexone, phentermine-topiramate, lorcaserin or the GLP-1 receptor agonist, liraglutide. However, these treatment approaches result in an average weight loss of ≤5 kg in clinical trials. The greater effectiveness of bariatric surgery, particularly Roux-en-Y gastric bypass, and sleeve gastrectomy clearly suggests that the stomach may play an important role in the control of appetite and food intake.
The sensory function of the stomach is, in part, determined by its motor functions such as tone and compliance, and by the rate of emptying. However, studies of gastric emptying in normal weight and obese persons have shown inconsistent results (reviewed in ref. 79). Gastric capacity was larger in obese persons when tested with an intragastric latex balloon filled with water. In contrast, other studies using the barostat or imaging (single-photon emission CT) techniques reported no differences in gastric volume or compliance between non-bulimic obese and lean subjects (reviewed in ref. 79). Recent studies from >500 patients ranging from normal body mass index (BMI) to class III obesity showed that gastric emptying of solids is faster and fasting gastric volume larger in obesity, confirming results in a prior, smaller study. In addition, other alterations in quantitative GI and behavioural traits associated with obesity were reduced satiation and satiety, altered body image, disorders of affect and reduced exercise. Principal component analysis identified latent dimensions that accounted for approximately 81% of the variation among overweight and obese subjects, including satiety or satiation (21%), gastric motility (14%), psychological factors (13%) and gastric sensorimotor factors (11%).
Increased body mass and fasting gastric volumes are independently associated with delayed satiation under standard laboratory conditions of food ingestion. Thus, Delgado-Aros and colleagues showed that, across a broad spectrum of BMI, there was an association between higher BMI, higher fasting gastric volume and decreased satiation (figure 4), manifested as reduced symptoms of fullness and a higher maximum tolerated volume of a nutrient drink ingested at a constant rate in a laboratory setting.
(Enlarge Image)
Figure 4.
Caloric intake at maximum satiation by gender and body mass index. There was higher caloric intake at maximum satiation in male subjects compared with women (left). Reproduced from ref. 82.
Figure 4 shows the higher maximum tolerated volume in obese compared with normal or underweight participants; an increase of 50 mL in the fasting gastric volume was associated with 114±32 kcal (479±134 kJ) more ingested at maximum satiation. These findings suggest that individuals with a higher BMI require more food to reach satiation (and, by inference, to signal termination of meal ingestion), and, over time, this results in higher caloric intake and weight gain (figure 4).
Other data support the importance of behavioural adaptation; thus, obese individuals have more severe symptoms of fullness, bloating, nausea and pain when reaching maximal satiation than individuals without obesity, and yet they continue to ingest calories, consistent with a behavioural adaptation to satiation. The additional understanding of the role of the stomach in obesity ushers in a new era when new medications, devices (such as balloons and drains or internal liners) and endoscopic interventions may prove more efficacious than the drugs targeting central mechanisms by targeting the GI functions that are critical for appetite and food intake.
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