Bariatric surgical procedures, including gastric bypass, vertical sleeve gastrectomy, and biliopancreatic diversion, are the most effective and durable treatments for obesity. In addition, These operations induce metabolic changes that provide weight-independent improvement in type 2 diabetes, fatty liver disease and other metabolic disorders. Initially thought to work by mechanical restriction of food intake or malabsorption of ingested nutrients, these procedures are now known to work through complex changes in neuroendocrine and immune signals emanating from the gut, including peptide hormones, bile acids, vagal nerve activity, and metabolites generated by the gut microbiota, all collaborating to reregulate appetite, food preference, and energy expenditure. Development of less invasive means of achieving these benefits would allow much greater dissemination of effective, gastrointestinal (GI)-targeted therapies for obesity and metabolic disorders. To reproduce the benefits of bariatric surgery, however, these endoscopic procedures and devices will need to mimic the physiological rather than the mechanical effects of these operations.
Key points
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Bariatric surgery causes durable weight loss by altering the physiologic regulation of body fat mass, demonstrating the critical role of the gastrointestinal (GI) tract in regulating energy balance and metabolic function.
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Mechanical restriction and macronutrient malabsorption do not appreciably contribute to the effectiveness of bariatric surgery.
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Bariatric surgery provides long-term benefit for patients with diabetes, fatty liver disease, and other metabolic disorders, through both weight loss–dependent and –independent mechanisms.
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Development of less invasive means of mimicking the effects of bariatric surgery could provide substantial benefit for a much greater number of patients.
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The mechanisms of action of bariatric surgery provides a valuable roadmap for the successful development and use of endoscopic, surgicomimetic therapies for obesity and related metabolic disorders.
Introduction
Of all the currently available treatments for obesity, bariatric surgery has by far the greatest efficacy. For the most commonly used procedures, vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), initial average weight loss is in the range of 35%, with approximately 75% to 80% of this weight loss maintained over an extended period, yielding an average weight loss in the range of 25% at 10 years. In addition, these gastrointestinal (GI) procedures have profound effects on metabolic disorders more broadly, inducing full or partial remission of diabetes and improvements in obstructive sleep apnea, fatty liver disease, hypertension, and dyslipidemia that are well beyond what is typically achieved with other antiobesity treatments. In typical patients with severe obesity and 1 or more comorbidities, bariatric surgery is associated with a dramatic decrease in overall mortality and mortality from diabetes, cardiovascular disease, and cancer. Despite these profound benefits, use of these procedures is severely limited. In the United States, approximately 200,000 patients undergo bariatric procedures each year, representing approximately 0.25% of all adults with obesity. This limited use reflects the invasive nature of bariatric surgery, potential complications, high cost, and incomplete reimbursement. These concerns are amplified by 2 additional factors: misunderstanding of both the pathophysiologic basis of obesity and the ability of surgery to ameliorate that pathophysiology. Surgery is widely perceived as forcing people to lose weight by limiting the amount of food that they can eat or the intestine’s ability to absorb ingested nutrients. If these were the mechanisms, the outcomes would be very poor, with insatiable hunger and unrelenting cravings the price of a healthier weight. This article shows that these are not the mechanisms, and perpetual misery is not the cost. Instead, bariatric surgery induces global changes in the powerful and complex network of mechanisms that determine and defend the body’s energy stores: the overall mass of body fat that is our living fuel tank. Obesity results from a combination of powerful environmental forces that induce the body to store an excess amount of fat, directly causing, exacerbating, and/or increasing the risk of developing more than 200 complicating or comorbid, diseases. Changes associated with modernization of the human environment have dramatically increased the number and intensity of these obesogenic forces over the past 150 years. Although genetics determine people’s susceptibility to these forces, few people are genetically resistant to obesity, and that resistance often fades with the normal effects of maturity, childbirth, and aging.
During the past 2 decades, much has been learned about the physiologic mechanisms and neurohumoral circuits underlying the normal and abnormal control of body fat mass, and the genes and mechanisms that determine susceptibility to obesity. However, the specific mechanisms by which changes in the modern environment induce and maintain obesity in susceptible individuals remain largely unknown. Nonetheless, the unique efficacy and durability of bariatric operations provides a positive control, a roadmap that could lead to a better understanding of the pathophysiology of obesity and guide the development of new, more effective strategies for its prevention and treatment. At a minimum, the profound effects of surgery, and the more recent recognition that these effects are grounded in physiology rather than physics, demonstrate the critical role of the GI tract in regulating and maintaining appropriate homeostasis in energy balance, fat mass, and metabolic function. Until the cellular and molecular mechanisms of these effects are more fully understood, finding less invasive means of manipulating the GI tract to induce the physiologic effects of surgery will likely provide the greatest near-term opportunity for such surgicomimetic treatment. Many early attempts at developing effective endoscopic treatments have failed. In some cases, these failures have resulted from unanticipated adverse events, but, in most cases, minimally invasive devices and procedures have not reproduced the dramatic benefits of surgery. Misunderstanding of the mechanisms by which bariatric surgery works can take clinicians down the wrong development path as they attempt to copy the physics without adequate attention to the physiology. Failure to recognize the multiplicity of manipulations and mechanisms inherent in most common bariatric procedures may blind clinicians to the need for combinations of less invasive treatments to achieve the power of surgery. Less invasive therapies do not need to be equal to surgery to provide important clinical value, but better understanding of how surgery works will almost certainly facilitate the path to devices and procedures that mimic the important benefits of surgery with profiles that allow for cost-effective treatment of a much larger portion of people with obesity, diabetes, and other metabolic disorders.
This review article summarizes current understanding of body weight and metabolic regulation and its implications for the causes and potential solutions to obesity and related diseases. It describes what is known about how surgery influences these metabolic processes and highlights specific cellular and molecular mechanisms induced by bariatric surgery that have recently been uncovered. In addition, recognizing that the effectiveness of surgery underscores the important metabolic regulatory role of the GI tract generally, it discusses how better understanding of surgical mechanisms could guide the development of new, more effective, and scalable GI-targeted therapies for these epidemic metabolic disorders, with particular attention to the development of effective endoscopic approaches.
Introduction
Of all the currently available treatments for obesity, bariatric surgery has by far the greatest efficacy. For the most commonly used procedures, vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), initial average weight loss is in the range of 35%, with approximately 75% to 80% of this weight loss maintained over an extended period, yielding an average weight loss in the range of 25% at 10 years. In addition, these gastrointestinal (GI) procedures have profound effects on metabolic disorders more broadly, inducing full or partial remission of diabetes and improvements in obstructive sleep apnea, fatty liver disease, hypertension, and dyslipidemia that are well beyond what is typically achieved with other antiobesity treatments. In typical patients with severe obesity and 1 or more comorbidities, bariatric surgery is associated with a dramatic decrease in overall mortality and mortality from diabetes, cardiovascular disease, and cancer. Despite these profound benefits, use of these procedures is severely limited. In the United States, approximately 200,000 patients undergo bariatric procedures each year, representing approximately 0.25% of all adults with obesity. This limited use reflects the invasive nature of bariatric surgery, potential complications, high cost, and incomplete reimbursement. These concerns are amplified by 2 additional factors: misunderstanding of both the pathophysiologic basis of obesity and the ability of surgery to ameliorate that pathophysiology. Surgery is widely perceived as forcing people to lose weight by limiting the amount of food that they can eat or the intestine’s ability to absorb ingested nutrients. If these were the mechanisms, the outcomes would be very poor, with insatiable hunger and unrelenting cravings the price of a healthier weight. This article shows that these are not the mechanisms, and perpetual misery is not the cost. Instead, bariatric surgery induces global changes in the powerful and complex network of mechanisms that determine and defend the body’s energy stores: the overall mass of body fat that is our living fuel tank. Obesity results from a combination of powerful environmental forces that induce the body to store an excess amount of fat, directly causing, exacerbating, and/or increasing the risk of developing more than 200 complicating or comorbid, diseases. Changes associated with modernization of the human environment have dramatically increased the number and intensity of these obesogenic forces over the past 150 years. Although genetics determine people’s susceptibility to these forces, few people are genetically resistant to obesity, and that resistance often fades with the normal effects of maturity, childbirth, and aging.
During the past 2 decades, much has been learned about the physiologic mechanisms and neurohumoral circuits underlying the normal and abnormal control of body fat mass, and the genes and mechanisms that determine susceptibility to obesity. However, the specific mechanisms by which changes in the modern environment induce and maintain obesity in susceptible individuals remain largely unknown. Nonetheless, the unique efficacy and durability of bariatric operations provides a positive control, a roadmap that could lead to a better understanding of the pathophysiology of obesity and guide the development of new, more effective strategies for its prevention and treatment. At a minimum, the profound effects of surgery, and the more recent recognition that these effects are grounded in physiology rather than physics, demonstrate the critical role of the GI tract in regulating and maintaining appropriate homeostasis in energy balance, fat mass, and metabolic function. Until the cellular and molecular mechanisms of these effects are more fully understood, finding less invasive means of manipulating the GI tract to induce the physiologic effects of surgery will likely provide the greatest near-term opportunity for such surgicomimetic treatment. Many early attempts at developing effective endoscopic treatments have failed. In some cases, these failures have resulted from unanticipated adverse events, but, in most cases, minimally invasive devices and procedures have not reproduced the dramatic benefits of surgery. Misunderstanding of the mechanisms by which bariatric surgery works can take clinicians down the wrong development path as they attempt to copy the physics without adequate attention to the physiology. Failure to recognize the multiplicity of manipulations and mechanisms inherent in most common bariatric procedures may blind clinicians to the need for combinations of less invasive treatments to achieve the power of surgery. Less invasive therapies do not need to be equal to surgery to provide important clinical value, but better understanding of how surgery works will almost certainly facilitate the path to devices and procedures that mimic the important benefits of surgery with profiles that allow for cost-effective treatment of a much larger portion of people with obesity, diabetes, and other metabolic disorders.
This review article summarizes current understanding of body weight and metabolic regulation and its implications for the causes and potential solutions to obesity and related diseases. It describes what is known about how surgery influences these metabolic processes and highlights specific cellular and molecular mechanisms induced by bariatric surgery that have recently been uncovered. In addition, recognizing that the effectiveness of surgery underscores the important metabolic regulatory role of the GI tract generally, it discusses how better understanding of surgical mechanisms could guide the development of new, more effective, and scalable GI-targeted therapies for these epidemic metabolic disorders, with particular attention to the development of effective endoscopic approaches.
Regulation of energy balance
There are 2 competing models of the regulation of human energy balance, fat mass, and body weight. The first and most widely held model is based on the voluntary regulation of calorie intake and expenditure, with obesity resulting primarily from a combination of overeating and inadequate energy expenditure from physical activity. According to this model, the human body uses all absorbed calories, either to perform cellular or physical work (including cellular growth and regeneration) or to store as body fat. This model predicts that there is little internal, or autonomic, regulation of energy balance and little opportunity to dump excess calories other than by means of physical exercise.
The second model of energy regulation is based on regulation of energy balance as a homeostatic control system, with the body seeking to maintain some form of appropriate balance in the setting of varied environmental conditions and influences. Under this model, ingestive behaviors and energy expenditure are regulated in response to physiologic state and metabolic demands. Modest, or even immodest, changes in food intake or physical activity are sensed by the endogenous regulatory machinery and compensatory mechanisms activated to maintain energy homeostasis. Under conditions of perceived energy deficit, this regulatory system induces increased food intake by increasing hunger, enhancing the reward value of nutrient-rich, high-calorie foods, and decreasing satiation and satiety. Nonessential energy expenditure is reduced, leading to a positive energy balance, net energy storage, and increased volume and mass of white adipose tissue, which is the body’s organ of energy storage. In contrast, under conditions of perceived energy sufficiency or excess, the reverse occurs, with decreased hunger, decreased reward value of food, enhanced satiation and satiety, and increased energy expenditure. This facultative increase in energy expenditure occurs through enhanced thermogenesis (oxidation of circulating and stored fats, generating heat that is radiated into the environment) and increased involuntary physical activity (nonexercise activity thermogenesis, including fidgeting).
These divergent models have important implications for the prevention and treatment of obesity. Under the first, calorie-centric, model, obesity is predicted to result directly from excess caloric ingestion or inadequate physical activity. Its proponents suggest that, in modern society, increased food availability leads to an increase in ingested calories, and the decreased necessity for physical activity leads to decreased caloric expenditure, together generating a positive energy imbalance, increased fat mass, and weight gain. Thus, under this model, the proposed solution is to eat fewer calories and increase physical activity. Because both of these behaviors are perceived to be fully under voluntary control, the high and growing prevalence of obesity suggests an epidemic failure of personal responsibility, generating the perception that people with obesity are intellectually, morally, or psychologically compromised and reinforcing the prevalent stigma against such individuals.
Under the second model, the body aims to maintain energy stores (ie, white adipose tissue mass) appropriate to the body’s physiologic state and uses regulation of both behavior and metabolic activity to do so. Obesity results from influences (endogenous or environmental) that cause this autonomic regulatory system to seek and defend inappropriately increased energy stores, thereby increasing fat mass and body weight and size. This model predicts that the most effective treatment of obesity will result from changing metabolic physiology so that the body’s desired energy stores are reduced to a more normal, physiologically appropriate range. Effective prevention strategies would be designed to block the influences that alter metabolic physiology in the first place.
Although both models likely contribute to the overall control of energy balance and the current epidemic of obesity, there is increasing evidence of the dominance of the second, autonomic regulatory model. As described later, some of the strongest evidence results from the profound beneficial effects of bariatric procedures and the growing understanding of their mechanisms of action. These mechanisms demonstrate the prominent role of the GI tract in the normal regulation of energy balance and metabolic function. They show the value of GI-targeted interventions in the effective prevention and treatment of obesity and related metabolic disorders. In addition, they can provide critical guidance to gastroenterologists and to those who seek to develop endoscopic, radiological, pharmacologic, or dietary therapies that mimic the mechanisms and effectiveness of bariatric surgery.
What causes obesity?
Obesity, like virtually all diseases, is caused by environmental influences acting on biologically susceptible individuals. Numerous studies have shown that predisposition or resistance to obesity is largely determined by genetic background. There are at least 10 genes in which mutations lead directly to obesity, but these monogenic obesities are exceeding rare. Far more commonly, modest variations in or around more than 100 other genes have been shown to alter an individual’s predisposition to obesity, and those whose genome includes multiple obesity-predisposing polymorphisms are likely to be at substantially increased risk. However, as has been widely noted, the rapid increase in the prevalence and severity of obesity cannot be explained by recent changes in people’s genetic background, so other factors must be operative. The obvious and most likely cause is a profound change in the modern environment, but what are these environmental factors? According to the widely held calorie imbalance model of fat mass regulation, obesity is caused by the combination of increased availability and therefore consumption of calories, combined with reduced physical activity–mediated energy expenditure. Proponents of this model suggest that evolution has favored protection against starvation rather than protection against obesity, with food scarcity serving as the major barrier to obesity in earlier times. However, this model has several flaws. During earlier times, when the human population was substantially smaller and natural plant-based and animal-based foods almost certainly as plentiful as they are now, scarcity-based barriers to excessive food intake would likely have provided inadequate protection. Although more physical labor was likely required to obtain nutrients, recent studies of primitive hunter-gatherer tribes show that the greater activity-based energy expenditure is offset by decreased thermogenesis, such that the daily total energy expenditure (TEE) of these naturally thin hunter-gatherers is no greater than that of sedentary members of modern society. Many studies have shown that even very modest selective advantage is sufficient for allelic exclusion over several generations, and the adverse physiologic effects of excessive body fat is certainly a sufficient selective disadvantage.
It is more likely that changes in the modern environment affect the normal physiologic apparatus that regulates energy balance and determines body fat stores. Such influences need not be calorie dependent; they only need to influence the signaling and biochemical mechanisms that underlie normal regulation of fat mass. Although researchers have not defined all of the potential environmental contributors, changes in 6 domains that are common to modernization in nearly all societies likely contribute to the ubiquitous growth of obesity across the globe:
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Alterations of the chemical content of foods, including processing to remove natural ingredients, add new chemical ingredients, decrease fiber and plant-based oligosaccharides, and increased nutrient homogeneity
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Increased availability and use of labor-saving machinery, which can lead to muscle dysfunction and diminished muscle-derived regulators of energy balance
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Sleep deprivation
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Disruption of circadian rhythms
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Increased speed and stress of modern life
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Obesity-promoting medications, including many used to treat common metabolic, cardiovascular, autoimmune, psychiatric, and infectious diseases
Bariatric surgical procedures
There are multiple effective types of bariatric and metabolic surgery, each with different anatomic and clinical implications. In addition, within each primary type of surgery, there are multiple versions that differ in subtle and not so subtle ways. This article focuses primarily on the major types, because they have generated the most clinical experience and have generally been subjected to the most carefully executed and controlled studies. All of these operations are now routinely performed using a laparoscopic approach, which has been shown to reduce hospital stay, the duration of bed rest, and the risk of wound infections and abdominal wall hernias. Otherwise, clinical outcomes after laparoscopically performed operations seem to be the same as for procedures performed via (open) laparotomy.
Roux-en-Y Gastric Bypass
This operation, depicted in Fig. 1 A , includes separation of a portion of the gastric cardia from the remainder of the stomach to create a small (typically 30–50 mL volume) gastric pouch, and transection of the proximal jejunum to midjejunum. The distal small bowel is brought up and anastomosed to the gastric pouch, providing an exit from the pouch directly into the midjejunum. The proximal side of the transected jejunum is anastomosed to the jejunum further down, providing an exit pathway for this biliopancreatic (BP) limb, which contains pancreatic and biliary secretions into the duodenum, as well as secretions and sloughed mucosa from the now nutrient-bare distal stomach (gastric remnant), duodenum, and proximal jejunum. As a result, after RYGB, ingested nutrients pass from the mouth (interacting with the oral mucosa and taste buds and activating the cephalic phase of the response to ingestion) to the esophagus to the small gastric pouch. They are then rapidly passed directly to the midjejunal Roux (or alimentary) limb for digestion, absorption, and further processing. The contents of the BP limb mix with those of the alimentary limb at the jejunojejunal (J-J) anastomosis, passing together into the common channel for further digestion, absorption/reabsorption, or passage to the colon for ultimate excretion. Even though it is now performed less commonly than VSG (discussed later), RYGB is considered the gold standard bariatric procedure, with an excellent risk-benefit profile for the treatment of obesity, type 2 diabetes, and several other obesity-related metabolic disorders.
Biliopancreatic Diversion
Conceptually, the BP diversion (BPD; see Fig. 1 B) is similar to that of an RYGB, with creation of a diminished gastric pouch that empties directly into the distal small intestine and a BP limb that joins the alimentary limb more distally. In the case of the standard BPD, the gastric antrum and pylorus are resected, leaving a much larger gastric pouch than is created during an RYGB but no gastric remnant at the proximal end of the BP limb. Both the alimentary and BP limbs are substantially longer than after an RYGB, leaving a relative short (typically 75–100 cm) common channel between the J-J anastomosis and the ileocecal valve. A variant of the BPD, commonly termed the duodenal switch (DS) procedure (see Fig. 1 C), includes creation of a narrow tubelike stomach by resection of the greater curvature of the stomach, and preservation of the pylorus between the stomach and alimentary limb. The small intestinal anatomy of the DS is essentially the same as in the standard version of the BPD. Because of the particularly long duodenal-jejunal bypass segment and short common channel, BPD is associated with an increased risk of malabsorption of macronutrients, as well as micronutrients (eg, minerals, vitamins, and other organic compounds) and therapeutic medications that depend on metabolism, transport, and/or absorption in the proximal small intestine. Because of the large interindividual variation in small intestinal length and function, the lengths of alimentary and BP limbs and common channel that provide optimal benefit with minimal malabsorptive risk are not well defined. Malabsorptive adverse effects can often be prevented or ameliorated by creating a longer (eg, ≥100 cm) common channel. However, because of the greater risk of associated metabolic and malabsorptive complications, BPD accounts for only about 2% of bariatric procedures.
Vertical Sleeve Gastrectomy
With its greater efficacy than RYGB, BPD, and its DS variant have been preferentially used by some surgeons for the treatment of patients with severe obesity (eg, patients with BMI >60 kg/m 2 ). However, because of the risks of major surgery in many of these heavier patients, several surgeons have opted for a 2-stage DS procedure, with the easier, and apparently safer, resection of the stomach vertical sleeve gastrectomy (VSG) allowing for initial weight loss, followed after several months by creation of the intestinal bypass anatomy. The dramatic effect observed in the first-phase operation (VSG) led several surgeons to propose using the VSG as an isolated bariatric procedure (see Fig. 1 C). This operation involves resection of the full greater curve of the stomach, leaving behind a banana-shaped or tube-shaped stomach. Despite loss of the grinding, or mill, function of the stomach and maintaining the pylorus intact, patients who have undergone a VSG show substantially more rapid gastric emptying. Because of its relative ease and excellent efficacy, the VSG has become the most commonly performed bariatric procedure, accounting for approximately 50% of all such operations worldwide and at least 65% of those performed in the United States.
Adjustable Gastric Banding
Adjustable gastric banding (AGB) (see Fig. 1 E) is the latest in a series of bariatric procedures designed to limit the effective size of the stomach, including horizontal, vertical, and vertical-banded gastroplasties. Using one of 2 FDA-approved adjustable banding devices, an AGB procedure includes placement of, the flexible, hollow device around the gastric cardia. The band is linked through an imbedded filling tube to a port placed subcutaneously in the abdominal wall. Filling of the device narrows the passage through which ingested food passes from the distal esophagus/gastric cardia into the gastric body, slowing the passage and potentially increasing ingestion-associated luminal pressure and/or wall stretch and tension proximal to the device, thereby stimulating mural mechanoreceptors. Initially very popular because of its easy placement and excellent initial safety profile, AGB has lost favor in recent years because of the modest associated weight loss, absence of weight loss–independent metabolic benefit, and risk of erosion into or through the gastric wall. At present, AGB accounts for approximately 5% of bariatric procedures in the United States and worldwide.
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