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).

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.