Fat Metabolism and Melanocortin 3 Receptors in African Americans

Our prior studies have found that children with homozygosity for two rare Melanocortin 3
Receptor (MC3R) polymorphisms (T6K+V81I) have greater fat mass compared to wild type
children. These polymorphisms are about 10-fold more prevalent in Non-Hispanic Black than
White Americans. In vitro, T6K+V81I causes MC3R hypofunction. Since mouse models and limited
human data suggest the MC3R may be involved in regulating substrate oxidation, and therefore
fatty acid disposal, we propose to study 30 Non-Hispanic Black BMI-matched subjects with
homozygous T6K+V81I or wild-type MC3R to compare substrate turnover (fatty acids and glucose)
during fasting and under conditions of hyperinsulinemia after adaptation from a normal-fat to
a high-fat isocaloric diet. Using adipocytes obtained from biopsies, we will also study
glucose and fatty acid uptake, storage and mobilization in vitro. We hypothesize that this
study will shed light on the role of the MC3R in substrate metabolism and energy expenditure,
and will yield information that may assist in the development of more effective approaches
for the treatment of obesity in Non-Hispanic Black Americans.

- INCLUSION CRITERIA

Volunteers will qualify if they meet the following criteria

1. Age 18-55 years. Subject age is limited to 55y maximum because subjects are required
to complete a maximal exercise test as part of their evaluations. Studying only
younger patients decreases the risks of such exercise tests.

2. Non-Hispanic Black by self-identification with (to the best of the subject s
knowledge) all 4 grandparents considered Non-Hispanic Black. Because T6K+V81I MC3R is
10-times more prevalent among Non-Hispanic Blacks, only Non-Hispanic Blacks will be
eligible to participate.

3. Obesity, defined as body mass index (BMI) (Bullet)30 kg/m2 and weight under 450 lbs,
in order for subjects to be able to undergo DXA scanning.

4. Willing to undergo genetic screening to establish that subject is either homozygous
wild type for MC3R or homozygous for T6K+V81I MC3R, with the absence of other genetic
causes of monogenic obesity (for both study and control groups).

5. Good general health. In general, subjects should take no medications. However,
individuals taking medications for obesity-related co-morbid conditions, who have not
had changes in dosage for more than 6 months, may be included, at the discretion of
the principal investigator.

6. For females, a negative pregnancy test at the initial evaluation. Because pregnancy is
a state in which weight gain is expected and appropriate, pregnant individuals would
not be suitable for this study. Sexually active women must be using an effective form
of birth control. These methods include abstinence, oral contraceptives, an
intrauterine device (IUD), levonogestrol implants (Norplant), or medroxyprogesterone
acetate injections (Depo-provera shots). If one of these cannot be used, contraceptive
foam with a condom is recommended (One of these methods must have been used by the
subject for at least two months prior to the start of the study).

EXCLUSION CRITERIA

Volunteers will be excluded (and referred to non-experimental treatment programs as needed)
for the following reasons:

1. Subjects with a major medical illnesses that in the opinion of the medical team would
impede interpretation of results, including significant renal, hepatic (other than
obesity-related steatosis), gastrointestinal, most endocrinologic (e.g., Cushing
syndrome, untreated hyper- or hypothyroidism, pheochromocytoma), hematological
problems (e.g. -PT/PTT values that are prolonged (Bullet) 3 seconds from the upper
limit of the normal or thrombocytopenia < 70,000) or pulmonary disorders; or
porphyria;

2. Current users of tobacco products;

3. Subjects following a diet with specific food requirements such as vegetarian, vegan,
or kosher;

4. Women who are pregnant or who are currently nursing an infant or have irregular
menses;

5. Individuals who have current substance abuse or a psychiatric disorder or other
condition that in the opinion of the investigators would impede competence or
adherence;

6. Recent (3 months) use of anorexiant medications;

7. Subjects using medications known to affect glucose and fatty acid metabolism and/or
absorption;

8. Subjects on anticoagulatns, or those who cannot safely stop NSAIDs or antiplataelet
agents for 10 days (a week prior to and three days after their biopsy)

9. Subjects with weight change of more than 3% of body weight in the past two months;

10. Subjects currently using a weight loss diet;

11. Subjects with untreated hypertension: a consistently (2 weeks apart) elevated systolic
blood pressure of greater than 160 mm Hg and/or a diastolic flood pressure greater
than 95 mm Hg.

12. Subjects with a history of keloid formation, since such individuals may have greater
scarring after biopsies or intravenous catheter placement.