Bariatric Surgery: The Road Ahead

The Metabolic Applied Research Strategy Initiative—Bariatric Surgery: Beyond Restriction and Malabsorption

Part 1: Bariatric Surgery: The Road Ahead

by Lee M. Kaplan, MD, PhD, and Randy J. Seeley, PhD

Abstract
The Metabolic Applied Research Strategy is a multi-year, multi-generational collaborative research program between the Massachusetts General Hospital, the University of Cincinnati, and Ethicon Endo-Surgery. Its focus is to interrogate and understand the physiologic and metabolic changes that occur after bariatric surgery (i.e., how bariatric surgery works to resolve conditions such as type 2 diabetes) with the goal of inventing new, less invasive, and less expensive treatments for patients suffering from obesity and its related health issues. In this article, which is the first in a series of articles published in Bariatric Times dedicated to the Metabolic Applied Research Strategy initiative, the authors discuss past and present beliefs on why bariatric surgery works, its true mechanisms of action, and how these findings might help researchers, surgeons, and industry harness the remarkable effectiveness of bariatric surgery.

LEE M. KAPLAN, MD, PhD
Lee M. Kaplan, MD, PhD, is Director of the Obesity, Metabolism & Nutrition Institute at Massachusetts General Hospital (MGH) and Associate Professor of Medicine at Harvard Medical School. He is the Director of the subspecialty Fellowship Program in Obesity Medicine and Nutrition at MGH; Associate Director of the NIH-sponsored Boston-area Obesity and Nutrition Research Center; a member of the NIH Clinical Obesity Research Panel; and past chairman of the Board of the Campaign to End Obesity. Dr. Kaplan’s clinical expertise is in the areas of obesity medicine, gastroenterology, and liver disease. His research program is focused on understanding the mechanisms by which the gastrointestinal tract regulates metabolic function and using physiological and genetic approaches to identify therapeutically relevant subtypes of obesity and its complications.

RANDY J. SEELEY, PhD

Dr. Randy J. Seeley is Professor of Medicine and holds the Donald C. Harrison Endowed Chair at the University of Cincinnati College of Medicine. In 2009, Dr. Seeley was appointed as the Director of the Cincinnati Diabetes and Obesity Center (CDOC). His scientific work has focused on the actions of various peripheral hormones in the central nervous system that serve to regulate food intake, body weight, and the regulation of circulating fuels. In particular, he focuses upon the numerous hypothalamic and gastrointestinal peptides and their associated receptors that influence both energy intake as well as peripheral metabolic processes with the aim of developing new treatment strategies for both obesity and diabetes.

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The growing epidemic of obesity and its myriad medical and economic complications have highlighted the limitations of the available therapeutic options. Statistically, lifestyle modification remains the most effective public solution for obesity in general. However, for individual patients with severe or medically complicated obesity, bariatric surgery provides the greatest, most reliable, and most durable benefit. Initially introduced in the 1950s and 1960s, numerous bariatric procedures have been developed with the goal of reducing food intake or causing malabsorption of ingested calories. This approach fit well with the then-perceived causes of obesity, including excessive food ingestion and inadequate physical activity. In recent years, however, we have become increasingly aware of the complexities of body weight regulation.

Obesity, the accumulation of excess body fat, results from imbalances in the physiological mechanisms that regulate nutrient intake and assimilation, energy balance, and metabolic function. Dysfunction of these powerful regulatory systems, whatever the cause, has proven extremely difficult to fix, making the effectiveness of bariatric surgery that much more remarkable.

So what is it about these gastrointestinal operations that allows them to generate such profound and durable weight loss, and how do they cause the dramatic improvements in diabetes and other metabolic disorders that disrupt the lives of so many people with obesity? Answering these questions is the goal of many basic and clinical scientists who believe that surgery holds the key to finding new, more effective therapies for obesity, diabetes, and other metabolic disorders.

Creating the Roadmap for Bariatric Surgery
As with many medical interventions, bariatric surgery is used simply because it works. How it works is interesting but fundamentally less important than the simple fact that it works. Indeed, the benefit-risk relationships of these operations are, and should be, the primary determinants of their clinical use. We must recognize that despite their powerful therapeutic benefits, bariatric surgical procedures also have risks that limit their use to people with the most severe or medically complicated obesity. Reducing these risks is one way to enhance the utility and acceptance of bariatric surgery. But there is also a need for more effective therapies for patients with obesity and metabolic disorders who should not, cannot, or will not undergo surgery. Whatever the mechanisms underlying the unique effectiveness of bariatric surgery, understanding and harnessing them is likely to open the door to such new, more effective, and less invasive treatments. The precise mechanisms of action of bariatric surgery, once determined, can be a “roadmap” for their development. The singular failure of other approaches in creating effective, nonsurgical treatments of obesity only increases the value of this approach.

More than Restriction and Malabsorption
Central to using bariatric surgery as a roadmap for the design of new therapies is establishing a more complete understanding of how these operations work. Early thinking was that they caused weight loss by mechanical restriction of food intake, malabsorption of ingested calories, or both. More recent observations, fueled in part by the apparent weight loss-independent effects of surgery on type 2 diabetes mellitus (T2DM), demonstrate that many forms of bariatric surgery directly, and beneficially, affect the body’s normal weight regulatory mechanisms. By altering endocrine, neural, and endoluminal signaling from the gut, these operations cause the body to seek a state of diminished fat storage and healthier metabolic function. In many cases, the responses to surgery include enhanced secretion and activity of hormones, such as glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and amylin, reduced secretion of ghrelin, altered activity of sympathetic and parasympathetic (e.g., vagus) nerves, and changes in the concentrations and dynamic responses of several luminal signaling factors, including bile acids, endocannabinoids, and metabolically important bacteria (microbiota) that reside within the body. The outlines of the complex, and exquisitely effective, mechanisms of bariatric surgery are only beginning to emerge, but one thing is clear—when they work, these operations change physiology at all levels. They change the body’s set point for fat storage; they change perceptions about hunger, satiety, and the reward value of food; they change behaviors in response to those perceptions; and they change the way the body processes ingested nutrients and regulates metabolic function. Indeed, there are few aspects of metabolic regulation that escape influence by these operations. These findings are both surprising and enabling. If the benefits of surgery came only from mechanical restriction and malabsorption, then the best we could hope for would be to find less invasive ways of changing gut structure.

Harnessing the Magic of Surgery
Because the effects are primarily physiological—physiological changes caused by physical manipulation—we can envision multiple new ways of harnessing the “magic” of surgery. Such novel approaches could include less invasive laparoscopic or endoscopic procedures, new therapeutic devices, medications, therapeutic foods and food supplements, and individually-targeted manipulation of the patient’s behavior or environment.

So, armed with this new information, how should we proceed? Many investigators have begun to elucidate components of the physiological response to surgery. These efforts have included numerous observational studies in human patients, and more recently, a growing effort that exploits animal models of bariatric surgery to reveal important mechanisms. Animal models are never identical to their human counterparts, but they can be powerful tools in the study of mechanism. We have already learned that all forms of bariatric surgery can be performed successfully in both large and small animals, and that their effects, even in mice, closely mimic their effects in our patients. These animal studies have revealed that most of the causes of obesity, diabetes, and other metabolic functions, and most of the effects of surgery to correct these disorders, are conserved across species. Using these animal models, we can develop and explore novel surgical procedures designed specifically to explore mechanisms of action, and by carefully manipulating the environments of these animals and using sophisticated pharmacological and genetic tools, we can explore how surgery works in ways that are simply not possible in our human patients. Overall, by combining these important advantages of animal studies with direct clinical and physiological assessment of our patients, we should be able to drive most efficiently toward a more complete mechanistic understanding.

Putting Research into Action
How can we use this developing understanding? As noted previously, all therapies for all diseases present some combination of benefit and risk to the patient. By understanding the mechanisms underlying both the benefits and risks of bariatric surgery, we should be able to find ways of enhancing the benefit of individual procedures without increasing their risk, or of decreasing the risk without reducing the benefit. Ways to achieve these goals in the future may include the following:
•    Predicting which patients will receive the most benefit from individual procedures and targeting those procedures to those patients
•    Predicting which patients will experience specific adverse events from individual procedures and taking steps to counter these effects
•    Designing therapies that preferentially treat one or more complications of obesity, such as diabetes, hypertension, cancer, or inflammatory disorders, and targeting those therapies to relevant patients
•    Using specific medications or other therapies to complement and enhance the physiological effects of specific operations
•    Developing novel, less invasive therapies, including more-limited surgical proecedures, medical devices, drugs, and combinations of these interventions, whose benefit-risk ratio favors their use in the enormous number of patients with less severe or medically complicated obesity.

Of the many ongoing efforts in this area, the Metabolic Applied Research Strategy (MARS) program supported by Ethicon Endo-Surgery (EES [Cincinnati, Ohio]) stands out.  MARS represents a comprehensive approach to the study of bariatric surgical mechanisms that combines intensive study of animal models with human studies of physiological response, outcome predictors, and clinical trials. The approach of the MARS program is to deconstruct these surgical procedures, better understand their mechanisms of action, and invent new ways of harnessing them. It represents an academic-industry collaboration unusual in its scope and unique in the area of bariatric surgery.

Over the next several months, a series of articles in Bariatric Times will describe various components of the MARS program and the new understanding about obesity, diabetes, and bariatric surgery that has resulted from these efforts. MARS is but one component of the worldwide effort to understand and use the mechanisms of bariatric surgery to improve the treatment of obesity and its many complications. Together with complementary programs supported by numerous health institutes and corporate partners across the world, the long-secret “magic” of bariatric surgery will become known and help us address the seemingly unstoppable epidemics of obesity and diabetes and their devastating consequences.

FUNDING: No funding was provided.

DISCLOSURES: Dr. Kaplan has received research support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIH), Ethicon Endo-Surgery, Merck Research Laboratories, and GI Dynamics. He has done consulting for C.R. Bard, Gelesis, Rhythm Pharmaceuticals, Medtronic, Sanofi-Aventis, Amylin Pharmaceuticals, Allergan, Merck, GI Dynamics, and Johnson & Johnson. Dr. Seeley has received research support, has done speaking or consulting for the following companies: Amylin Pharmaceuticals, Eli Lilly, Johnson & Johnson, Novo Nordisk, Zafgen Inc., Merck, Roche, Alkermes, and Pfizer.

Category: MARS Initiative Series, Past Articles