Diet-Induced-Obesity Resistant Phenotypes in Humans

While many obesity studies focus on the individuals who are already overweight and obese, a
complementary approach to understand such a common disease is to define the mechanisms which
allow some lean individuals to resist weight gain. The predominant cause of human obesity is
the inheritance of genes favoring fat storage and efficient energy utilization interacting
with an obesogenic environment, characterized by readily available, energy-dense food and
sedentary lifestyle. However, a persistent percentage (about 30%) of the US adult population
remains thin (BMI <23 kg/M(2)). While some of these individuals maintain their weight by
vigilantly controlling their diet, exercising or taking medication(s), others may have the
ability to remain thin despite an excessive energy intake and without volitional exercise. To
identify these individuals and define their phenotypes will provide unique insights into
energy and body weight homeostasis, and may yield novel approaches for treating obesity.

In this natural history protocol, we will recruit and characterize a cohort of
constitutionally lean and healthy adult volunteers (age 25-50, BMI 18.5-25 kg/M(2)) who do
not have pathological or exogenous factors that are known to stimulate energy expenditure,
suppress food intake, or decrease absorption. We will recruit volunteers who are
weight-stable, sedentary, and non-restrictive eaters, characterize their free-living dietary
and physical activity energy expenditure using food records and portable accelerometers,
respectively. Using an inpatient controlled setting, we will carefully characterize the
details of their 24-hr energy metabolism, body composition, core and skin temperatures, and
blood chemistries while they are on a one-week metabolic diet adjusted to maintain his/her
body weight (baseline) vs. another week of higher energy intake level (1000 extra kcal per
day above their baseline). Overfeeding will continue for two more weeks in the outpatient
setting with all meals provided by our metabolic kitchen, followed by the fourth week of
overfeeding and repeated measurements back in the inpatient setting. We hypothesize that
spontaneous changes in energy expenditure and/or calorie intake may differ between
individuals, and such difference may explain the ability for some to resist body gain. The
accruals of humans with obesity-resistant phenotypes will significantly enhance our
understanding of the mechanisms of energy homeostasis and identify potential novel regulators
for controlling obesity.

- INCLUSION CRITERIA:

1. Healthy normal men and women between 25-50 years of age;

2. BMI between 18.5 and 25.0 kg/M(2);

3. Self-reported as having had trouble gaining weight, who doing little or no
exercise, self-described or by friends or family members as an overeater, and who
have never tried to lose weight.

EXCLUSION CRITERIA:

1. A self-reported history of overweight after the age of 18, other than during pregnancy
for women;

2. Recent weight changes >2% of current body weight in the last 6 months;

3. Current or past history of eating disorders such as binge eating, anorexia nervosa, or
bulimia, by psychological evaluations;

4. Current or past history of intentional weight loss by self-report, other than
postpartum weight loss;

5. High physically demanding occupations or volitional exercise >20 total minutes/day of
moderate intensity or higher (as measured by sweating), >2 days/week, by self-report;

6. Significant dietary limitations (multiple food allergies/intolerances, vegan diet,
etc.) that may affect absorption and body weight, or special dietary requirements that
are difficult to accommodate with by study diets;

7. Significant physical limitations that may preclude completing the majority of the
tests in this study;

8. Current pregnancy, recent pregnancy (<3 years), current/recent breast feeding (<1
year), or perimenopausal status. During the study, women may be asked to use birth
control and will undergo repeated pregnancy testing. Subjects who refuse these tests
will be excluded;

9. Current or past medical conditions that are known to affect energy metabolism and body
weight regulations, including HIV/AIDS, cancer, cardiac ischemia, dyslipidemia,
thyroid and parathyroid disorders, hypo- or hypertension, diabetes (type 1 or type 2)
or impaired glucose tolerance, congenital or acquired lipodystrophy, hepatic, renal,
neuromuscular, celiac disease and other malabsorptive conditions, known genetic
disorders that alter lipid metabolism, or cardiac failure as assessed by history and
physical exam;

10. Any psychiatric condition (including psychosis) or personality disorder as judged by
the PI or Co-PI that would impede participation in the study;

11. Smoking (currently or within the past year), excessive caffeine (>500 mg/day) and/or
alcohol intake (>2 drinks/day for men, > 1 drink/day for women), as assessed by self
reports and serum thiocyanate;

12. Taking narcotics, cocaine, or marijuana which would alter metabolism (positive urine
toxicology screen)

13. Any use of medications or nutritional supplements known to increase EE, depress food
intake, or affect absorption;

14. Unwilling or unable to give informed consent;

15. Any other clinical or sub-clinical conditions not mentioned above that are considered
by the investigators as significant exclusions for the study.