Thomas Wadden - US grants

This application is for a Research Scientist Development Award, Level I. The application describes a comprehensive program of training and research in the field of obesity and weight regulation. The proposed training in the areas of 1) regulation of food intake and body weight, 2) energy expenditure and clinical nutrition, and 3) body composition will contribute significantly to my scientific development and enable me to complete the proposed research more successfully. The research proposed in this application will examine three primary issues: 1) the long-term treatment of obesity in adults by very-low-calorie diet and behavior therapy; 2) the treatment of obesity in black adolescent females; and 3) the prevention of obesity in young children through a school-based intervention. The study on the treatment of obese adults will examine resting energy expenditure and body composition to determine if they are adversely affected by very-low-calorie diet (420 kcal/day). In particular, we will determine whether the prolonged use of a very-low-calorie diet reduces energy expenditure and lean body mass in a fashion that renders maintenance of weight loss more difficult. Changes in body composition will also be examined in the teenagers in the second study. It is important to demonstrate that youngsters do not lose vital lean body mass will dieting. This is the first major study of the treatment of obesity in black children. The school-based program for the prevention of obesity continues a line of investigation that our research team has been pursuing for the past several years.

DESCRIPTION (Adapted from the Applicant's Abstract): This is a competing continuation application for a Research Scientist Development Award that was received in July 1987. The goal of the proposed research is to improve the treatment of significantly obese women (30 percent or more overweight) by conducting two randomized trials -- one primarily of exercise and the other of diet. Both studies will assess not only changes in weight but also changes in body composition, resting metabolic rate (RMR) and eating behavior, all of which may affect long-term weight control. A third study will examine the effects of weight cycling. The specific aims of each study are: 1) To determine whether resistance/strength training will prevent reductions in fat-free mass and RMR occurring with weight loss and, thus, improve long-term weight control. A total of 128 women will be randomly assigned to four conditions: a) diet alone; b) diet plus aerobic training, c) diet plus strength training; and d) diet combined with aerobic and strength training. Subjects will be treated for 1 year and followed for a second. 2) To assess the effectiveness of portion - and calorie controlled foods in 120 women randomly assigned to three conditions: 1) a 1200 kcal/d liquid diet; 2) a 1200 kcal/d diet of conventional foods; or 3) a 1200 kcal/d mixed diet, consisting of a liquid diet combined with an evening meal of food. The study will examine the hypothesis that liquid diets are initially effective because they facilitate excellent adherence, but are associated with rapid regaining of weight because of subjects' binge eating when they resume consumption of convention foods. This study will provide the first controlled evaluation of a mixed diet that resembles a popular meal-replacement plan and that is expected to capture the benefits of liquid diets while avoiding their drawbacks. 3) To assess the adverse effects of weight loss and regain in 119 women previously treated in our clinic. The candidate wishes to test the hypothesis that weight loss followed by full weight regain is associated with: 1) an increased percentage of body fat; 2) a lower RMR; and 3) increased problem eating (i.e., binge eating). The candidate's scientific development will be facilitated by visits with colleagues who will provide expertise in: 1) strength training and the measurement of energy expenditure during activity; 2) binge eating; 3) measurement of energy expenditure using doubly labeled water; and 4) methodological issues in weight cycling. The proposed research will provide rich training experiences for two postdoctoral fellows, two psychology graduate students, and several psychiatric residents who will collaborate on the studies.

Obesity is one of our nation's most serious health problems. The treatment of this disorder experienced a serious setback last year when two popular weight loss medications -- fenfluramine and dexfenfluramine -- were withdrawn from the market because of concerns that they were associated with valvular heart disease. Despite this unfortunate occurrence, it appears that pharmacotherapy will play an increasingly important role in the management of obesity in the next decade. In November 1997, the Food and Drug Administration approved sibutramine, a serotonin and norepinepherine re-uptake inhibitor, for "weight loss and maintenance of weight loss". Orlistat, a gastric and pancreatic lipase inhibitor, is now being considered for similar approval, with several other medications likely to follow. Previous studies indicate that optimal weight losses and improvements in health are likely to be obtained when behavioral and pharmacologic interventions are combined. Behavior therapy facilitates adherence to exercise and medication recommendations, whereas pharmacotherapy, by reducing hunger and increasing satiety, aids efforts to consume a reduced calorie diet. Long-term pharmacotherapy also holds promise of improving the maintenance of weight loss, a shortcoming of behavioral treatment. The proposed study will examine, in an 18-month trial, the separate and combined effects of behavior therapy and pharmacotherapy for obesity. A total of 296 obese men and women (BMI greater than 32 kg/m2) will be randomly assigned to one of four conditions: 1) Medication (i.e., sibutramine) Plus Standard Care; 2) Medication Plus Individual Behavior Modification (provided by a physician in brief visits); 3) Medication Plus Group Behavior Modification; or 4) Group Behavior Modification Alone. We predict that subjects treated by medication, combined with either individual or group behavior modification, will achieve significantly greater weight losses and improvements in health than those treated by Medication Plus Standard Care. This will result from the latter subjects' significantly better adherence to diet, exercise, and medication recommendations. We also predict that subjects treated by medication plus behavior modification (in individual or group sessions) will achieve significantly greater weight losses (particularly during the last 9 months) than persons who receive Group Behavior Modification Alone. If confirmed, the above findings will have important implications for treating obesity in primary care.

Obesity is one our nation's most serious public health problems. Weight losses as little as 5-10 percent of initial weight are frequently sufficient to improve health complications of this disorder. Most obese individuals are able to achieve reductions of this size by following a program of diet and lifestyle modification. The great majority, however, regain one-third of their weight loss in the year following treatment, with increasing regain over time. Evidence from a variety of studies indicates that regular exercise is associated with improved maintenance of weight loss, as well as with enhanced fitness and health. Despite these benefits, obese (and average weight) individuals report numerous barriers to exercise, including inadequate time and beliefs that it is associated with exhaustion, physical discomfort, and potential embarrassment. As a result, adherence to structured exercise programs is far from optimal. Lifestyle activity may be a preferable alternative to traditional exercise. It offers a more flexible approach to increasing physical activity by increasing walking throughout the day, taking stairs rather than escalators, and generally decreasing reliance on energy-saving devices. Two studies of children showed that lifestyle activity was superior to structured exercise in facilitating the maintenance of weight loss. The goal of the proposed research is to improve the maintenance of weight loss by increasing physical activity in individuals who participate in a comprehensive behavioral weight loss program. A total of 216 obese adults (108 males, 108 females) will be randomly assigned to one of three conditions: 1) structured on- site exercise; 2) structured at-home exercise; or 3) lifestyle activity. Subjects will be treated for 40 weeks and then followed through week 104. We predict that, at week 104, subjects in the lifestyle condition will maintain their end-of- treatment weight losses significantly better than those in the two other conditions and will have significantly greater improvements in health and psychosocial status. This will result from their maintaining significantly higher levels of physical activity during the follow-up period. The predicted superiority of lifestyle activity is based on extensive pilot data and, if confirmed, should significantly improve the management of obesity and its associated health complications.

DESCRIPTION (provided by applicant): This application represents a competitive renewal of a Mid-career Investigator Award in Patient-Oriented Research (K24) for "Improving the Effectiveness of Obesity Management." The renewed award will provide the candidate 40% effort for each of the next 5 years to further his mentoring of postdoctoral researchers and junior faculty and to continue his research to improve the treatment of obesity. Postdoctoral researchers will be provided intensive, individual clinical and research training and will have the opportunity to collaborate on the candidate's current NIH-funded studies. The first is a multi-site randomized controlled trial (N = 390) to improve the management of obesity in primary care practice, with treatment delivered by primary care physicians and medical assistants (UO1-HL087072). This award was secured with pilot data collected during the original K24 award. The second trial is the Look AHEAD study that is assessing the long-term health consequences of intentional weight loss and increased physical activity in overweight individuals with type 2 diabetes (U01-DK57135). A third study is investigating whether binge eating disorder (BED) impairs weight loss in persons who undergo bariatric surgery (R01-DK069662). The candidate will support postdoctoral researchers in initiating their own investigations and mentor them through the stages from formulating a suitable question to publishing their results. He will similarly facilitate the research of junior faculty who are supported by Mentored Patient-Oriented Research Awards (K23) and similar mechanisms. All trainees will be encouraged to take advantage of training opportunities provided by the University's new Institute for Diabetes, Obesity, and Metabolism, as well as other labs on campus that address obesity and its co-morbidities. The renewed award also will support the candidate's efforts to conduct two pilot studies that use functional magnetic resonance imaging (fMRI) to study changes in neural activation that may occur following bariatric surgery. The effects of BED will be examined, as will those of two different surgeries. PUBLIC HEALTH RELEVANCE: Renewal of the K24 award will provide the candidate time and effort to mentor postdoctoral researchers and junior faculty concerning the causes and consequences of obesity, as well as the prevention and treatment of this condition. The award also will support the candidate's efforts to examine potential changes in appetite centers in the brain that may occur after weight loss surgery.

DESCRIPTION (provided by applicant): Nearly five percent of Americans now suffer from extreme obesity, defined by a body mass index (BMI) >= 40 kg/m 2. This condition is associated with dire health and economic consequences that make weight reduction imperative. Bariatric surgery is the most effective intervention for extreme obesity and will be sought this year by approximately 125,000 individuals. The gastric bypass (GBP) reduces initial body weight by an average of 25 percent to 30 percent; however, treatment outcome is variable. A substantial minority of individuals fails to achieve significant weight loss, and even more regain weight two or more years after surgery. As a result, leading bariatric surgeons recommend that surgical candidates undergo a behavioral (psychiatric) evaluation to identify those with psychosocial contraindications. There are few data, however, to inform patient selection or the need for postoperative counseling. Binge eating disorder (BED) is common among extremely obese individuals and is arguably the most likely behavioral complication to affect the outcome of bariatric surgery. BED is characterized by the consumption of an objectively large amount of food and the experience of loss of control during overeating episodes. It also is associated with increased symptoms of depression and other psychopathology. The proposed research will address critical gaps in our knowledge concerning whether binge eating disorder negatively affects the outcome of GBP, either by limiting weight loss or by increasing the rate of postoperative behavioral complications (including vomiting and dumping). These findings should guide patient selection and the provision of postoperative counseling. The study, in turn, will reveal the effects of GBP on binge eating, energy and macronutrient intake, appetite, and physical activity. Changes over 30 months in patients with (N = 80) and without BED (N = 80) will be compared with each other but also with changes in a group of comparably obese individuals with BED who are treated by a traditional behavioral weight control program. Inclusion of this latter group (N = 50) will more fully reveal the behavioral risks and benefits of GBP. The study, by examining ghrelin and other appetite-related hormones, also will enhance knowledge of the regulation of body weight following GBP.

DESCRIPTION (provided by applicant): Look AHEAD is randomized clinical trial examining the long-term health effects of an intensive weight loss intervention in approximately 5,145 overweight volunteers with type 2 diabetes. Participants are randomized to an intensive lifestyle intervention designed to achieve and maintain weight loss by decreased caloric intake and increased physical activity, or to a control program of diabetes support and education. The primary outcome of Look AHEAD is the aggregate occurrence of severe cardiovascular events (fatal and non-fatal Ml and stroke and cardiovascular deaths) over a planed follow-up of 11.5 years. The original grant application provided funding for the first 7 years of the study (1 year for study design and 6 for execution of the trial). The present grant application is for an additional 7 years of funding to complete the Look AHEAD trial. All aspects of the study have proceeded extremely well - the sample of 5,145 was recruited on time;retention has been excellent and the intervention has been effective in producing initial weight loss and maintaining it over time. All 16 clinical sites have been successful in recruitment, retention, and delivery of the intervention and the DSMB has been very positive about the execution of the trial. The present application reviews the overall design of Look AHEAD, progress to date, and plans for the future. Specific Aims are to retain the cohort over time, continue to complete annual in-person visits and semi-annual telephone interviews for outcome assessments and continue to administer the lifestyle intervention. These procedures will enable us to analyze the effects of the intervention on serious cardiovascular- related factors and complications, and cost-effectiveness of the intervention.

DESCRIPTION (provided by applicant): Bariatric surgery is the most effective weight loss option for persons with extreme obesity (i.e., body mass index = 40 kg/m2). Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) are the most common bariatric procedures, and they induce long-term reductions of ~25% and ~15% of initial weight, respectively. Anatomical differences resulting from the two procedures are associated with postoperative differences in endocrine functioning. In particular, the orexigenic hormone, ghrelin, is generally suppressed in RYGB and increased in LAGB patients. Furthermore, postprandial increases in the satiety factors, glucagon-like peptide 1 (GLP-1) and peptide YY (PYY3-36), are significantly increased after RYGB, compared with LAGB. Each of these appetite-regulating hormones has been found to act in brain regions related to both the homeostatic and hedonic control of food intake. A separate literature has examined neural activation in feeding centers, as measured with functional magnetic resonance imaging (fMRI) and positron emitted tomography (PET), in response to food cues. Most of these studies have compared responses to images of high-calorie vs. low-calorie foods or non-food items. Some have further compared responses in lean vs. obese individuals. Generally, high-calorie food images stimulate activation in the prefrontal cortex, mesolimbic dopamine system (e.g., ventral-tegmental area and nucleus accumbens), and other limbic areas (e.g., orbitofrontal cortex, amygdala, insula, and cingulate cortex). Furthermore, responses are greater in obese vs. lean individuals. Fewer studies have examined neural response to meal consumption;those investigations have found that many of the same regions are activated by nutrient ingestion. The proposed research is a prospective observational study that seeks to integrate two areas of inquiry: 1) endocrine effects of bariatric surgery;and 2) neural response to food cues and feeding. Patients who undergo RYGB or LAGB, and matched obese controls who do not seek weight loss, will complete assessment visits at 0, 6, and 18 months, which include: 1) a fMRI scan while viewing high- and low-calorie food images in the fasted state;2) a perfusion MRI scan to measure cerebral blood flow in the fasted state;3) fasting blood draw;4) consumption of a liquid test meal;5) serial perfusion MRI scans to assess the effects of the meal;and 5) serial blood draws to assess postprandial changes in ghrelin, GLP-1, and PYY3-36. Comparisons of changes among the three groups at 6-months and 18-months follow-up will comprise our primary analyses. The primary hypotheses are that following surgery: 1) fMRI response to high-calorie food images will be reduced in RYGB vs. LAGB patients and controls;2) RYGB patients will show larger increases in postprandial GLP-1 and PYY3-36 (accompanied with a blunted postprandial ghrelin response) than will LAGB patients and controls;and 3) RYGB patients will demonstrate a greater postprandial increase in resting brain activity in homeostatic and hedonic feeding areas than will LAGB and control participants. PUBLIC HEALTH RELEVANCE: The proposed research is an 18-month prospective observational study of extremely obese patients who seek laparoscopic adjustable gastric banding (LAGB) or roux-en-Y gastric bypass (RYGB) surgery. Using functional and perfusion magnetic resonance imaging, we will assess changes in neural response to food cues and meal ingestion 6 and 18 months after surgery. Changes in the two surgical approaches will be compared with each other and with those in a group of extremely obese individuals who do not seek weight loss. In addition, we will serially measure postprandial changes in appetite-regulating hormones and examine the relationships between neural and endocrine response to food consumption.