Gastrointestinal Hormonal Regulation of Obesity

Obesity is a major cause of morbidity and mortality within the VA medical system accounting for the majority of cases of diabetes mellitus, hypertension, coronary artery disease and cerebrovascular accidents. An improved understanding of the regulation of body weight in Veteran obese patients will improve the quality of life by avoidance of serious medical complications and by suggesting novel therapeutic approaches. The large proportion of the Veteran population that frequent the VA health care system and who suffer from obesity or have obesity-related illnesses can benefit from this research. Obesity is associated with early mortality in the United States. It has been estimated to result in about 280,000 deaths per year in U.S. adults and the expenses related to obesity are in excess of $80 billion. Obesity is a major cause of morbidity and mortality within the VA medical system accounting for the majority of cases of diabetes mellitus, hypertension, coronary artery disease and cerebrovascular accidents. The proposed studies will address important physiological questions regarding the mechanisms of gut peptides regulating satiety and food intake, as well as provide potentially important clinical treatment strategies. The release of GI hormones in response to meal stimuli plays an important role in the regulation of body weight homeostasis. The neural pathways interconnecting gut signaling of satiety to the brain in response to nutrient intake are regulated by neuropeptides and GI hormones. The investigators have a long history in the study of GI hormones. In the current application, the investigators plan to elucidate the impact of a high protein diet on the profile of gut hormones released postprandially in obese subjects and the underlying changes at the neuronal (vagal afferent) level that take place in response to a high protein diet in a relevant experimental model. Understanding the regulatory mechanisms involved in satiety will provide clues for existing and novel forms of therapies. Studies may also provide insight into underlying mechanisms responsible for weight loss induced by gastroplasty and bariatric procedure used for the treatment of obesity. The study design is a three-group randomized, controlled study. This randomized controlled study lasting 24-30 months will assign approximately 198 volunteer subjects (ages 30, BMI 27-40 kg/m2) (66 subjects each) to the following three groups who will adhere to diets with the same number of calories: 1. Very high protein diet group based on 1.4 gram of protein per pound of lean body mass, 2. High protein diet group based on 1 gram of protein per pound of lean body mass, and 3. Standard protein diet group as control based on 0.5 gram protein per pound of lean body mass with same calories. All participants will meet with a Registered Dietitian (who it is anticipated will join the research study team), to assist them with their diet efforts in all the arms. In the study, the percent energy from fat will be held constant at 30% and the differences in the diets relate only to the protein and carbohydrate contents (35% protein and 35% carbohydrate, 25% protein and 45% carbohydrate, and 12.5% protein and 57.5% carbohydrate respectively). The investigators will assess the efficacy of a high protein diet on satiety and pattern of postprandial gut hormone in obese patients. All the subjects will be followed by a dietitian and determination of circulating gut hormone and biochemical assays will be performed.