Gastrointestinal Hormonal Regulation of Obesity
Gastrointestinal Hormonal Regulation of Obesity
The objective of this study is to test and determine whether a high protein diet is
 efficacious, safe and beneficial to curtail food intake and body weight in obese adult human
 patients and to establish whether neurohormonal mechanisms of a high protein diet induce an
 early signal of fullness or satiety in a relevant experimental model, focusing on activation
 of gastric vagal afferents.
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).

 We 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.
Inclusion Criteria:

 For inclusion in the study, patients must fulfill all of the following criteria:

 -  Subjects must be able to attend all 7 scheduled study visits at the West LA GI clinic
 at the VAGLAHS, not including the screening visit.

 -  Subjects must sign the VA Greater Los Angeles Healthcare System Institutional Review
 Board approved written informed consent prior to the initiation of any study-related
 activities or study specific procedures or randomization.

 -  Subjects must have given written authorization for the release of protected health
 information in compliance with Health Insurance Portability and Accountability Act
 (HIPAA) regulations.

 After the Informed Consent process, these additional Inclusion Criteria will be applied to
 potential subjects:

 -  Age 30 years and older at screening.

 -  BMI of 27 to 40 kg/m2 inclusive.

 -  Subjects must be in good health as determined by medical history, physical examination
 performed by the Investigator (Study doctor) at the Screening stage, and screening
 clinical laboratory tests including chemistry panel and CBC.

 -  Must have stable smoking habits (or be non-smokers) for at least 6 months prior to
 screening and agree not to intend to change such habits during the course of the
 study.

 -  Subjects requiring the regular use of any prescription medication may be admitted to
 the study, providing the dose is stable.

 -  Subjects must be able to communicate and cooperate with the Principal Investigator and
 the staff and willing to comply with the study instructions.

 Exclusion Criteria:

 -  Weight instability: Subjects reporting weight change of greater than 3.0 kg in the
 month prior to screening.

 -  Any subject who has been on a very low calorie diet (less than 800 kcal/day) for a
 period of 4 months or more in the 12 months prior to screening, or who has lost
 greater than 10 kg in the 6 months prior to screening.

 -  Any subject who has a history of diabetic gastroparesis or gastric emptying disorder
 as indicated in the potential subject's medical history and VA's Computer Patient
 Record System (CPRS).

 -  Use of any other investigational drug(s) within 8 weeks prior to screening.

 -  Subjects should not have received antibiotics within the prior 4 weeks of screening.

 -  Abnormal laboratory parameters:

 -  Serum creatinine greater than 1.6 mg/dL;

 -  Liver function tests, alanine transaminase (ALT), alanine transaminase (AST),
 Bilirubin results greater than 2.0 times the upper limit of normal;

 -  Triglycerides greater than 500 mg/dL;

 -  Total cholesterol greater than 350 mg/dL;

 -  Thyroid-stimulating hormone (TSH) outside of normal range disorder, as indicated in
 the potential subject's medical history, the VA's Computer Patient Record System
 (CPRS) and laboratory tests performed during the screening process.

 -  Subjects who drink more than 1 alcoholic beverage per day (that is: 1 beer; or 1 glass
 of wine; or 1 shot of liquor).

 -  Pregnant women or women likely to become pregnant during the course of the study may
 not participate in this study. Female subjects must not be able to conceive by reason
 of surgery, radiation, one year past the onset of menopause, or an approved method of
 contraception.

 -  No vulnerable subjects will be included in the study.