Metabolic Applied Research Strategy Initiative (MARS): Understanding Why Bariatric Surgery Works

| November 11, 2010

An Interview with Principal Investigators
Lee M. Kaplan, MD, PhD, and Randy Seeley, PhD

About MARS
The Metabolic Applied Research Strategy (MARS) is a multi-year, multi-generational research program led by Ethicon Endo-Surgery to 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). The approach is to deconstruct current procedures in order to understand their mechanism of action and then leverage this understanding to reinvent less invasive and less expensive treatments for patients suffering from obesity and related health issues.

The goal of this interview is to discuss with key researchers involved in the effort the implications of the initiative, current and future research, and their predictions for how the findings will change treatments for obesity and other metabolic diseases.

Bariatric Times. 2010;7(11):13–15

Lee M. Kaplan, MD, PhD, is Director of the MGH Weight Center and the Obesity Research Center at Massachusetts General Hospital 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 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 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 to develop new treatment strategies for both obesity and diabetes.

What is the Metabolic Applied Research Strategy (MARS) initiative? How did it start?
MARS is a comprehensive effort to develop the next generation of effective therapies for obesity and related metabolic disease. Recognizing that gastrointestinal weight loss surgery (bariatric surgery) provides the most effective, long-term treatment of these disorders, the MARS program aims to determine the mechanisms underlying the strong therapeutic benefits of these operations and use that mechanistic information to design novel therapies to treat them. By catalyzing the development of less invasive therapies that mimic the effectiveness of bariatric surgery, MARS aims to enable effective treatment of a much broader segment of the population affected by obesity, diabetes, and other chronic metabolic disorders. The large and growing worldwide epidemic of obesity and its medical complications, the limited application of bariatric surgery itself (in the United States, approximately 1 in 400 adults with obesity undergo bariatric surgery each year), and the limited long-term effectiveness of nonsurgical therapies for these disorders generate a vast unmet need that the MARS initiative aims to address.

How is the work being done for the MARS initiative important to metabolic and bariatric surgery?
Understanding the mechanisms by which bariatric surgical procedures exert their powerful therapeutic effects will facilitate the development of novel therapies that mimic these effects but are less invasive so that they can be used to treat a much larger portion of the population with obesity, diabetes, and related diseases. In addition, as good as bariatric surgery is, it is not completely effective in resolving obesity and metabolic disorders in all patients. By fostering better understanding of the mechanisms, and therefore the limitations, of these procedures, the MARS initiative will also facilitate the development of novel therapies that can complement the effects of surgery and therefore enhance the effectiveness of the procedures currently in use. Finally, one of the goals of the MARS initiative is to identify predictors of outcome after each of the commonly used bariatric surgical procedures. Doing so will allow improved matching of patients with the appropriate surgical procedure, leading to better outcomes overall and thereby improving the cost- and risk-benefit profile of current treatments for obesity, diabetes, and related metabolic disorders.

What are the goals of the MARS initiative?
The overall goal of the MARS initiative is to enhance the options for the effective treatment of obesity, diabetes and other metabolic disorders by 1) applying current and emerging bariatric procedures more effectively, 2) developing means of enhancing the effectiveness of current and emerging bariatric procedures, and 3) developing novel, less invasive therapies that exploit the powerful mechanisms unleashed by bariatric surgery. To achieve these goals, the MARS initiative uses preclinical and clinical science to advance our understanding of the mechanisms by which current and emerging bariatric surgical procedures exert their profound therapeutic effects on obesity, diabetes, and other metabolic disorders (including lipid disorders, inflammatory disorders, selected cancers, and neurological dysfunction). The scientific investigations included in the MARS program rely heavily on animal models of bariatric surgical procedures, the manipulation and study of which will facilitate the most rapid advances in our understanding. In addition, by incorporating broad-scale genetic and metabolic investigation of the outcomes of surgery in both human patients and animal models, the MARS program aims to develop improved means of determining which patients will benefit most from each of the available and emerging therapies.
The goals of the MARS initiative are to develop new therapies for obesity and its related comorbidities that are less invasive and reach more patients than we reach today. Additionally, we want to understand how to identify which patients should receive which procedures.

What are some challenges you have faced or will face during your research?
Obesity, diabetes, and related metabolic disorders result from defects in highly complex physiological systems. Because of the complexity of these systems, disturbances in them are notoriously resistant to treatment (hence the very limited effectiveness of available lifestyle and pharmacological therapies). The remarkable effectiveness of bariatric surgical procedures indicates that they have the ability to correct these disturbances; however, we now know that these surgical procedures are effective because they simultaneously influence numerous components of these regulatory systems. The sheer complexity of the systems involved provides a challenge to understanding the underlying mechanisms. Because of the many physiological effects of these operations, an additional challenge is identifying which of these effects are most critical. It is the most critical effects of these operations that need to be included in novel, less invasive therapies. The complexity of the physiology provides a particular technical challenge for the MARS research effort. Bariatric surgery exerts its effects in many organs across the body. Understanding its complex mechanisms requires experiments in whole animals (as opposed to isolated cells and molecules) and the use of complex surgical models in these animals. By their nature, these types of studies are technically challenging, expensive, and time-consuming, underscoring the need for a program as comprehensive as the MARS initiative.

Scientific discovery always involves risks. The key challenges here involve how to pick the appropriate rodent models that will best answer the scientific questions and translate appropriately to the patients we are striving to help.

The MARS initiative explores the physiological as well as the mechanical reasons of why bariatric surgery works—why is it important to study both aspects?
Recent data from the MARS initiative have demonstrated that most of the effects of bariatric surgery result from changes in neuroendocrine physiology caused by the surgical manipulations. Although these operations have long been thought to work mechanically (e.g., by physical restriction of food intake and/or blockage of nutrient absorption), we now know that most of the effects are physiological. These findings provide important opportunities for the development of effective but less invasive therapies. If surgery worked primarily by mechanical means, the best we could hope for would be to reproduce those mechanical changes using less invasive technologies (e.g., endoscopy or interventional radiology). Since the primary effects of surgery are physiological, we have the additional opportunity to develop therapies that mimic the physiological changes of surgery without altering the anatomy of the gastrointestinal (GI) tract. This approach of “bypassing the bypass” could be done with medical devices, medications, therapeutic foods, or combinations of these approaches. Importantly, each type of bariatric operation appears to improve obesity, diabetes, and other metabolic disorders through distinct mechanisms. Understanding the mechanisms of each of these procedures is therefore likely to yield a wide variety of novel and effective therapeutic approaches.

To only think of these surgeries as mechanical interventions greatly limits the ability to innovate new ways to achieve effective therapy. Once we identify the key physiological drivers of these surgical effects, it will open the door to many new potential surgical interventions.

What specific areas of research are you working on?
Dr. Seeley and I are two Principal Investigators on the MARS preclinical program. My group is examining the mechanisms of action of RYGB and related procedures. For these studies, we are using several different rat and mouse models of bariatric procedures. The effects of surgery in these animal models are very similar to their effects in human patients. By using the models, however, we can explore outcomes (good and bad) and physiological and molecular mechanisms in much more detail. In particular, in combination with the surgery itself, we are able to use pharmacological, genetic, dietary, and other environmental manipulations to determine how RYGB and other bariatric procedures are able to improve obesity, diabetes, and other metabolic disorders so profoundly. Using these approaches, we are studying several of the myriad effects of surgery, including its effects on the brain, the liver, the pancreas, muscle, and the GI tract itself. It is likely that all of these effects acting together account for the effectiveness of these procedures and need to be considered in the design of new therapies that enhance the effectiveness of bariatric surgery or provide less invasive alternatives to surgery that provide similar benefits. In additional studies within the MARS initiative, our group is attempting to identify clinical, physiological, and genetic predictors of response to each of these procedures so that individual patients can be more effectively matched with the procedure most appropriate for them. Dr. Seeley is leading efforts aimed at increasing the understanding of why other metabolic procedures, such as vertical sleeve gastrectomy (VSG) and laparoscopic greater curvature plication (LGCP), work.

What results have your research yielded thus far? Based on preliminary results, do you have any predictions for what you may find during future research?
Results of our component of the MARS project, to date, fall into the following three categories: 1) better understanding of the mechanisms of bariatric surgical procedures on obesity and diabetes, 2) identification of promising new approaches that harness this understanding, and 3) identification of strategies to predict outcomes after these procedures so as to improve the risk-benefit and cost-benefit relationships for these most effective interventions. From a mechanistic perspective, we have identified the important roles of increased energy expenditure in response to bypass-type bariatric procedures (e.g., gastric bypass, duodenojejunal bypass, biliopancreatic diversion) that distinguishes these operations from the purely gastric interventions (banding, sleeve gastrectomy, and LGCP). In parallel, we have identified and have begun to characterize the important role of bile acids in mediating aspects of changes in both food intake and energy expenditure after these procedures. We have defined the important role of GLP-1 in selectively mediating the antidiabetic effects of gastric bypass and identified additional hormonal contributors to outcomes after GI interventions broadly. From a therapeutic perspective, we have developed novel means of stimulating energy expenditure directly, developed new, effective strategies for synergistically combining bariatric surgery with other approaches, and identified several molecular targets for novel therapies.

How do you predict the findings in the MARS initiative will change the treatments used for obesity and metabolic diseases?
In the first instance, the identification of clinically relevant predictors of response to different bariatric surgical procedures will allow better matching of patients with the appropriate therapy. Implementing this strategy will improve the risk-benefit and cost-benefit profiles of individual procedures and of obesity treatment as a whole. Thereafter, findings from the MARS initiative will facilitate the development of therapies that can complement and thereby extend the efficacy of currently available treatments of obesity, diabetes, and other metabolic disorders. The rational development of combination therapies for these disorders is likely to be a major benefit of the MARS approach. Finally, many of the preclinical studies within MARS are identifying novel targets for obesity and metabolic therapy, as well as means of influencing those targets effectively. By “reverse engineering” the most effective therapies for obesity, including gastric bypass, sleeve gastrectomy, LGCP, gastric banding, and other bariatric procedures, we can identify the mechanisms of their effects and mimic them with far less invasive interventions. Through this comprehensive process, we anticipate better use of current therapies; development and use of an expanded array of combination therapies; and development of several effective, novel therapies that can be used alone or in combination to treat obesity and its complications.

How do you predict the findings in the MARS initiative will change prevention methods of obesity and metabolic diseases?
Understanding the mechanisms by which bariatric surgery is as effective as it is will provide critical information in two areas. First, it will help discern which of the many molecules and physiological pathways involved in energy balance and metabolic function are most sensitive to disruption (leading to reversal of obesity and related metabolic disorders). This information will provide a unique window into those aspects of obesity that are most amenable to effective intervention. In parallel, studies within the MARS initiative to identify predictors of outcome in different patients will help identify clinically relevant subtypes of obesity. Together, these two approaches will facilitate the matching of patients with therapies that are likely to provide them with the greatest benefit. The knowledge gained from this effort will also facilitate a more rational basis for developing and using prevention strategies. The wide variability of patients with obesity suggests that effective prevention strategies will need to be tailored to different patient subtypes, an approach that is a logical extension of the efforts within MARS to develop more effective and individualized therapies for obesity and its many metabolic complications.

The MARS initiative will allow for a much wider array of potential treatment options. Those options will encompass a much larger range of different mechanisms and then match those mechanisms to patients with much greater affinity than we do today.

How might the results now and in the future impact patient care and access to care?
One of the most immediate effects of the MARS effort is likely to be the development of a more rational approach to choosing obesity therapy for individual patients, with a consequent improvement in risk-benefit and cost-benefit profiles of obesity therapies overall. These developments will enhance the health and economic benefits of obesity therapies, giving a stronger incentive for payors to provide coverage for them. This development will likely enhance coverage for obesity treatment overall, thereby increasing access to effective care. In addition, through the development of novel, minimally invasive therapies and improved combination therapies, results from the MARS initiative are likely to increase the portion of people with obesity who have access to effective treatments. Given the high prevalence of obesity and the large burden of associated disease, these effects will likely lead to an improvement in the health and wellbeing of the population overall.
We all know that the enormous numbers of patients suffering from obesity means that are many patients we currently do not help. New methods that can help reduce costs will increase access to effective treatments for a much wider range of patients.

Financial 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 C.R. Bard, Gelesis, Rhythm Pharmaceuticals, Medtronic, Arena Pharmaceuticals, 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,  and Alkermes.

Category: Interviews, Past Articles

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