Obesity is a leading cause of illness and death worldwide. It is a risk factor for many common gastrointestinal symptoms and digestive disorders, including many cancers. Disruption of mechanisms that regulate appetite and satiety are fundamental to the development of obesity. Knowledge of these issues that are discussed in this article will provide the basis to develop health strategies to prevent obesity-related diseases.
Obesity is a leading cause of illness and death worldwide. It is one of the greatest public health challenges of this century, with more than 1.6 billion adults classified as being overweight and 400 million as obese. From 1980 to 2002, rates of obesity more than doubled in the United States, reaching 32% in the adult population, thus achieving the highest rates of obesity in the developed world. Although overall obesity rates began to plateau in the 2000s, severe obesity in adults and children has continued to increase. The most dramatic increases have occurred in class III obesity (body mass index [BMI] ≥40), with an increase from 0.78% in 1990 to 2.2% in 2000.
As the rates of obesity have escalated, it is more than just waistbands that have expanded. Obesity is a risk factor for some of the most prevalent diseases in North America, including coronary artery disease, stroke, diabetes mellitus, hypertension, and osteoarthritis. Moreover, common digestive disorders, such as gastroesophageal reflux, esophagitis, nonalcoholic fatty liver, gallstones, and certain cancers, arise with greater frequency in obese individuals compared with normal-weight individuals ( Table 1 ).
| Magnitude of Increased Risk with Obesity (Compared with Normal or Low BMI) | Comments | |
|---|---|---|
| Esophagus | ||
| GERD symptoms | 50% | |
| Erosive esophagitis | 50%–100% | |
| Barrett esophagus | 2-fold | Abdominal obesity |
| Adenocarcinoma | 2-fold | |
| Gallbladder | ||
| Stones | 2- to 3-fold | More in women |
| Cancer | 35%–85% | More in women |
| Pancreas | ||
| Worse acute pancreatitis | 20%–50% | |
| Cancer | 35%–85% | Abdominal obesity |
| Colon | ||
| Adenoma | 50%–100% | |
| Cancer | 2-fold | Colon (not rectum), more in men, more with abdominal obesity, postmenopausal women |
| Liver | ||
| Nonalcoholic fatty liver disease | 2- to 4-fold | Abdominal obesity |
| Advanced HCV-related disease | 50% | |
| Cirrhosis | 30%–50% | |
| Hepatocellular carcinoma | 17%–89% | |
Obesity-related health care costs have also ballooned. Americans who are obese now make up a quarter of the population and are responsible for a 40 billion-dollar rise in annual medical spending. On average, an obese person spends more than 1400 dollars for his or her medical care annually, almost 42% more than is spent by a nonobese person. Although there are no current recommendations for testing in the absence of symptoms or preexisting laboratory abnormalities, weight loss is a recommended strategy to prevent the symptoms that are related to obesity-related gastrointestinal disorders and to decrease the risk of progression of diseases.
Gastrointestinal symptoms related to obesity and obesity treatments
Generally defined as a BMI of 30 kg/m 2 or more (less accurate in body builders and pregnant women), obesity has been linked to a wide range of gastrointestinal symptoms. Disruption of mechanisms that regulate appetite and satiety is fundamental to the development of obesity. Acid regurgitation, heartburn, and diarrhea are some symptoms that are reported with increased frequency in obese subjects compared with normal-weight subjects ( Table 2 ). Pharmacologic and surgical treatments of obesity, by altering gastrointestinal function through mechanisms that regulate hunger, food intake, or absorption of nutrients, influence the energy consumed and meal termination.
| Symptoms | Body Mass Index Category | |||
|---|---|---|---|---|
| Overweight | Obese | |||
| OR a | 95% CI | OR a | 95% CI | |
| Upper gastrointestinal symptoms | ||||
| Abdominal pain | 0.90 | (0.66, 1.23) | 1.29 | (0.93, 1.78) |
| Fullness | 0.90 | (0.55, 1.46) | 0.89 | (0.52, 1.53) |
| Food staying in the stomach | 1.37 | (0.91, 2.07) | 1.76 | (1.15, 2.7) |
| Bloating | 0.98 | (0.73, 1.33) | 1.07 | (0.77, 1.48) |
| Acid regurgitation | 2.00 | (1.39, 2.86) | 3.39 | (2.36, 4.87) |
| Heartburn | 1.64 | (1.16, 2.31) | 3.11 | (2.20, 4.39) |
| Nausea | 0.70 | (0.35, 1.40) | 1.46 | (0.77, 2.75) |
| Vomiting | 1.05 | (0.59, 1.87) | 1.70 | (0.96, 3.02) |
| Dysphagia | 0.53 | (0.30, 0.95) | 0.66 | (0.36, 1.18) |
| Lower gastrointestinal symptoms | ||||
| Anal blockage | 0.63 | (0.41, 0.99) | 0.74 | (0.46, 1.17) |
| Diarrhea | 1.35 | (0.97, 1.88) | 1.64 | (1.16, 2.32) |
| Constipation | 0.72 | (0.47, 1.11) | 0.50 | (0.30, 0.85) |
| Lumpy/hard stools | 0.99 | (0.72, 1.37) | 0.49 | (0.33, 0.75) |
| Loose/watery stools | 1.09 | (0.78, 1.53) | 1.63 | (1.15, 2.29) |
| Fecal urgency | 1.09 | (0.77, 1.54) | 1.46 | (1.03, 2.09) |
| Fecal incontinence | 0.98 | (0.66, 1.46) | 1.36 | (0.91, 2.04) |
a Odds ratio (95% CI) from logistic regression model adjusting for age, gender, binge-eating category, physical activity score, and version of the survey; relative to normal weight.
Gut hormones and regulation of appetite and satiety
There are 3 primary mechanisms that control appetite: 1) the hypothalamus serves as the center for the integration of feeding and associated neuroendocrine and gastrointestinal activities; 2) the gastrointestinal tract provides a rich source of hunger and satiety factors that modulate meal intake and termination ; and 3) adipose-derived leptin is involved in the long-term regulation of energy intake and expenditure.
The gastrointestinal tract is the largest endocrine organ in the body. Gut hormones exert exocrine actions, regulate the secretion of insulin, and central nervous system circuits that control food intake, and influence gut motility. They interact with the brain via the gut-brain axis through which they modulate peptide neurotransmitter release via hypothalamic and brainstem centers ( Fig. 1 ). Apart from ghrelin, most gut peptides known to influence appetite, including insulin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), oxyntomodulin (OXM), cholecystokinin (CCK), and pancreatic polypeptide (PP), do so by inducing satiety and some also by affecting intestinal motility.
Ghrelin, a hormone that is synthesized primarily in the epithelial P/D1 cells of the gastric fundus, is an agonist of the growth hormone receptor and a member of the motilin-related family of regulatory peptides. Ghrelin stimulates appetite and induces a positive energy balance, thus leading to body-weight gain in addition to its ability to stimulate growth hormone secretion and to accelerate gastric motility. Ghrelin modulates the synthesis and secretion of several neuropeptides in the hypothalamus that stimulate feeding and regulate related hypothalamic functions. Unique among gut hormones, plasma ghrelin levels gradually increase with fasting and decrease immediately after a meal, supporting a role in meal initiation. Plasma ghrelin levels also increase with diet-induced weight loss, which suggests that ghrelin may act to counter diet-induced weight loss by invigorating hunger and increasing energy intake.
Insulin is secreted by the Islets of Langerhans in the pancreas to promote storage of energy; its circulation is increased in response to food intake and in states of obesity. Insulin receptors are expressed in the CNS and injections of insulin into the brain of insulin-deficient animals can markedly reduce eating behavior. Adipocyte-derived leptin an important anorexigenic hormone that like insulin, is involved in long-term energy homeostasis. Leptin is secreted in response to a positive energy balance, and circulated to the hypothalamus and other regions of the brain inducing negative feedback responses. The actions of ghrelin and leptin are complimentary, yet they are antagonistic in that they modulate appetite, gastric motility, and body weight by counterregulating the same hypothalamic signals, neuropeptide Y (NPY) and agouti-related peptide (AgRP). NPY and AgRP are two extremely potent orexigenic peptides of the arcuate nucleus (AR) within the hypothalamus that together act to reduce energy expenditure. In addition to the inhibition of orexigenic neurons within the AR, leptin also stimulates the activity of proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), two anorexigenic hypothalamic neurons that contribute to increased thermogenesis and energy expenditure. Within the AR these anatomically distinct neuronal populations provide overlapping projections to other key parts of the hypothalamus implicated in the control of feeding. As a therapeutic agent, leptin held great promise. However, exogenous administration of supraphysiologic doses of leptin failed to produce any notable diminution in appetite or weight loss. To date, obesity-related resistance to the action of leptin has limited its therapeutic effectiveness.
GLP-1, which is coreleased postprandially with PPY and OXM from L cells of the small intestine in proportion to the amount of energy consumed, acts as a powerful incretin, enhancing meal-related insulin secretion. Clinically, long-acting GLP-1 receptor agonists (such as exendin-4) facilitate glucose control by several different mechanisms, promote a subtle yet prolonged satiety effect, and improve glycemic control when used as adjunctive therapy in patients with type 2 diabetes receiving metformin. GLP-1 has been shown to delay gastric emptying and intestinal transit time. Gastrointestinal inhibitory peptide (GIP), another incretin peptide, is secreted from K cells in the duodenum and proximal jejunum in the presence of glucose and fat within minutes of food ingestion. Although GIP promotes energy storage through direct action on adipose tissue, it is not known to have an effect on food intake.
PYY3-36, the major form of PYY, reduces acute food intake in normal-weight humans by modulating appetite circuits in the hypothalamus. PYY has high affinity for the Y2 family of receptors of the hypothalamus, and it inhibits orexiant NPY neurons, activates anorexiant POMC neurons and α-MSH hormone, and may contribute to its anorectic effect through actions on the vagus and brainstem. The physiologic effects of PYY3-36 include delayed gastric emptying and reduced gastric secretion, and PYY has been implicated as a major constituent of the ileal brake.
Digestion of lipids results in the release of PP, the amount secreted being proportional to the calorie content of the meal. PP is considered a long-term appetite suppressant with peripheral administration in obese mice, resulting in reduced food intake and slowed weight gain. The mechanism that mediates PP satiety effect remains unknown, although it is known to stimulate the Y2 receptors in the hypothalamus and may directly activate neurons in regions of the AR. The actions of OXM are to diminish gastric secretion and reduce food intake when administered centrally to rodents or peripherally to rodents or humans. OXM increases energy expenditure by more than 25% and reduces food intake, body weight, and adiposity in rodents. A discrete receptor for OXM has not been identified, yet OXM does bind to the GLP-1 receptor and has been shown to cause similar patterns of central neuronal activation after peripheral administration.
The anorexiant effect of CCK was recognized more than 30 years ago. CCK is synthesized by L cells of the small intestine and secreted in the proximal duodenum. CCK-1 receptors are primarily expressed by vagal afferent neurons, the targets by which CCK is thought to produce the sensation of satiety. The half-life of CCK is just 1 to 2 minutes, suggesting it may serve as a short-term regulator of appetite. Animal studies have shown administration of CCK to reduce food intake but increase meal frequency without affecting the body weight. Biologic functions of CCK include delayed gastric emptying, stimulation of pancreatic enzyme secretion, and gallbladder contraction.
Circulating levels of these gut hormones and those of the central nervous system can be affected by increased or decreased adiposity, pharmacotherapy, and gastrointestinal bypass surgery.
Gut hormones and regulation of appetite and satiety
There are 3 primary mechanisms that control appetite: 1) the hypothalamus serves as the center for the integration of feeding and associated neuroendocrine and gastrointestinal activities; 2) the gastrointestinal tract provides a rich source of hunger and satiety factors that modulate meal intake and termination ; and 3) adipose-derived leptin is involved in the long-term regulation of energy intake and expenditure.
The gastrointestinal tract is the largest endocrine organ in the body. Gut hormones exert exocrine actions, regulate the secretion of insulin, and central nervous system circuits that control food intake, and influence gut motility. They interact with the brain via the gut-brain axis through which they modulate peptide neurotransmitter release via hypothalamic and brainstem centers ( Fig. 1 ). Apart from ghrelin, most gut peptides known to influence appetite, including insulin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), oxyntomodulin (OXM), cholecystokinin (CCK), and pancreatic polypeptide (PP), do so by inducing satiety and some also by affecting intestinal motility.
Ghrelin, a hormone that is synthesized primarily in the epithelial P/D1 cells of the gastric fundus, is an agonist of the growth hormone receptor and a member of the motilin-related family of regulatory peptides. Ghrelin stimulates appetite and induces a positive energy balance, thus leading to body-weight gain in addition to its ability to stimulate growth hormone secretion and to accelerate gastric motility. Ghrelin modulates the synthesis and secretion of several neuropeptides in the hypothalamus that stimulate feeding and regulate related hypothalamic functions. Unique among gut hormones, plasma ghrelin levels gradually increase with fasting and decrease immediately after a meal, supporting a role in meal initiation. Plasma ghrelin levels also increase with diet-induced weight loss, which suggests that ghrelin may act to counter diet-induced weight loss by invigorating hunger and increasing energy intake.
Insulin is secreted by the Islets of Langerhans in the pancreas to promote storage of energy; its circulation is increased in response to food intake and in states of obesity. Insulin receptors are expressed in the CNS and injections of insulin into the brain of insulin-deficient animals can markedly reduce eating behavior. Adipocyte-derived leptin an important anorexigenic hormone that like insulin, is involved in long-term energy homeostasis. Leptin is secreted in response to a positive energy balance, and circulated to the hypothalamus and other regions of the brain inducing negative feedback responses. The actions of ghrelin and leptin are complimentary, yet they are antagonistic in that they modulate appetite, gastric motility, and body weight by counterregulating the same hypothalamic signals, neuropeptide Y (NPY) and agouti-related peptide (AgRP). NPY and AgRP are two extremely potent orexigenic peptides of the arcuate nucleus (AR) within the hypothalamus that together act to reduce energy expenditure. In addition to the inhibition of orexigenic neurons within the AR, leptin also stimulates the activity of proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), two anorexigenic hypothalamic neurons that contribute to increased thermogenesis and energy expenditure. Within the AR these anatomically distinct neuronal populations provide overlapping projections to other key parts of the hypothalamus implicated in the control of feeding. As a therapeutic agent, leptin held great promise. However, exogenous administration of supraphysiologic doses of leptin failed to produce any notable diminution in appetite or weight loss. To date, obesity-related resistance to the action of leptin has limited its therapeutic effectiveness.
GLP-1, which is coreleased postprandially with PPY and OXM from L cells of the small intestine in proportion to the amount of energy consumed, acts as a powerful incretin, enhancing meal-related insulin secretion. Clinically, long-acting GLP-1 receptor agonists (such as exendin-4) facilitate glucose control by several different mechanisms, promote a subtle yet prolonged satiety effect, and improve glycemic control when used as adjunctive therapy in patients with type 2 diabetes receiving metformin. GLP-1 has been shown to delay gastric emptying and intestinal transit time. Gastrointestinal inhibitory peptide (GIP), another incretin peptide, is secreted from K cells in the duodenum and proximal jejunum in the presence of glucose and fat within minutes of food ingestion. Although GIP promotes energy storage through direct action on adipose tissue, it is not known to have an effect on food intake.
PYY3-36, the major form of PYY, reduces acute food intake in normal-weight humans by modulating appetite circuits in the hypothalamus. PYY has high affinity for the Y2 family of receptors of the hypothalamus, and it inhibits orexiant NPY neurons, activates anorexiant POMC neurons and α-MSH hormone, and may contribute to its anorectic effect through actions on the vagus and brainstem. The physiologic effects of PYY3-36 include delayed gastric emptying and reduced gastric secretion, and PYY has been implicated as a major constituent of the ileal brake.
Digestion of lipids results in the release of PP, the amount secreted being proportional to the calorie content of the meal. PP is considered a long-term appetite suppressant with peripheral administration in obese mice, resulting in reduced food intake and slowed weight gain. The mechanism that mediates PP satiety effect remains unknown, although it is known to stimulate the Y2 receptors in the hypothalamus and may directly activate neurons in regions of the AR. The actions of OXM are to diminish gastric secretion and reduce food intake when administered centrally to rodents or peripherally to rodents or humans. OXM increases energy expenditure by more than 25% and reduces food intake, body weight, and adiposity in rodents. A discrete receptor for OXM has not been identified, yet OXM does bind to the GLP-1 receptor and has been shown to cause similar patterns of central neuronal activation after peripheral administration.
The anorexiant effect of CCK was recognized more than 30 years ago. CCK is synthesized by L cells of the small intestine and secreted in the proximal duodenum. CCK-1 receptors are primarily expressed by vagal afferent neurons, the targets by which CCK is thought to produce the sensation of satiety. The half-life of CCK is just 1 to 2 minutes, suggesting it may serve as a short-term regulator of appetite. Animal studies have shown administration of CCK to reduce food intake but increase meal frequency without affecting the body weight. Biologic functions of CCK include delayed gastric emptying, stimulation of pancreatic enzyme secretion, and gallbladder contraction.
Circulating levels of these gut hormones and those of the central nervous system can be affected by increased or decreased adiposity, pharmacotherapy, and gastrointestinal bypass surgery.
Related posts:
Prevalence and Epidemiology of Gastrointestinal Symptoms Among Normal Weight, Overweight, Obese and Extremely Obese Individuals
Colonic Complications of Obesity
The Surgical Treatment of Metabolic Disease and Morbid Obesity
Short- and Long-Term Surgical Follow-Up of the Postbariatric Surgery Patient
Gastrointestinal Symptoms and Diseases Related to Obesity: An Overview
Colonic Complications of Obesity
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