Adaptive Responses to Overfeeding and Weight

The persistent problem of weight regain following weight loss is perhaps the most significant
barrier to addressing the current obesity epidemic. The biological drive to regain weight
following weight loss is due in part to increased appetite leading to increased energy intake
(EI) and reductions in energy expenditure (EE) in part due to changes in energy expended in
physical activity (PA). These physiological adaptations to weight loss are most relevant
during episodes of dietary indiscretion resulting in overfeeding (OF) when reduced obese (RO)
people fail to respond to the state of positive energy balance in a way that maintains the
reduced state. There is increasing evidence that RO individuals who exercise (RO-Ex) are less
like to regain as compared to RO individuals who are sedentary (RO-Sed). Previous studies
were conducted on the effects of OF on EI, EE, PA and fat metabolism in non-obese individuals
either prone (OP) or resistant to obesity (OR). Subjects were then followed for 5 years to
measure weight change. These studies showed that differences in the response of nocturnal fat
oxidation and higher levels of moderate/vigorous PA following OF correlated with 5 year
weight gain suggesting that these factors were potentially important mechanisms for weight
gain. Previous work has shown that measures of hunger fail to suppress with OF in RO
individuals and that nocturnal fat oxidation is reduced in RO-Sed but maintained in RO-Ex
following a day that included a bout of exercise. This study will look at the responses of
EE, EI, PA and fat metabolism to OF (40% above basal energy for 3 days) in obese, RO-Sed and
RO-Ex men and women and correlate these responses to weight change over the subsequent year.
The hypothesis is that changes in the response of one or more of these variables to OF will
correlate with weight regain. The Significance of the studies lies in the fact that subjects
will begin to clarify the metabolic mechanisms that underlie a propensity for weight regain
in RO individuals. Innovation: The proposed studies will systematically examine a range of
responses to OF and prospectively correlate them with weight gain while taking into account
aspects of behavior relevant to weight regain. The hope is that these studies will lay a
foundation for future studies that will examine the mechanisms underlying specific adaptive
responses that directly relate to weight regain and help with the design of strategies to
address and/or respond to these processes.

Inclusion criteria.

- BMI of 30-38 kg/m2 and weight stable over the previous 6 months.

- Satisfied with current weight and not planning to lose weight at the time of
enrollment (persons with obesity control group) -or- not satisfied with current weight
and motivated to lose weight at the time of enrollment (reduced obese groups)

- No more than 90 min or 3 bouts of planned physical activity/wk.

- Pass a medical and physical screening performed by the study physician.

- Reporting a habitual, regular sleep-wake cycle for the month preceding screening that
involved going to bed between 2200 and 0100 h and getting up between 0600 and 0900 h
with >7 h and <9.25 h in bed.

- Live or work within 45 minutes of the CU-AMC (reduced obese groups only) (exceptions
may be made at the discretion of the Study PI on a case by case basis for highly
motivated subjects).

- Own a smartphone (Android or Apple iOS).

- For Females

- Not currently pregnant or lactating

- Not pregnant within the past 6 months

- Not planning to become pregnant in the next 12 months; sexually active women of
childbearing potential may be enrolled if they use a reliable means of contraception

- Capable and willing to provide informed consent, understand exclusion criteria, and
accept the randomized group assignment (reduced obese groups)

Exclusion criteria.

- Being considered unsafe to participate as determined by the study physician;

- Taking medications affecting weight, triglycerides, or energy intake/energy
expenditure in the last 3 months;

- Having abnormal blood chemistry and/or hematology as deemed significant by the study
physician;

- Ever having a history of systemic, psychiatric, neurological disease, or drug and
alcohol abuse;

- History of cardiovascular disease, diabetes, uncontrolled hypertension, untreated
thyroid, renal, hepatic diseases, dyslipidemia or any other medical condition
affecting weight or lipid metabolism;

- Score > 18 on Beck Depression Index (BDI) will require further assessment by the study
physician to determine if it is appropriate for the subject to participate in the
study;

- Use of a continuous positive airway pressure (CPAP) device for the treatment of
obstructive sleep apnea (OSA). A score of >10 on the Epworth sleepiness scale or >5 on
the Pittsburgh Sleep Quality Index will require further assessment by the study
physician to determine if it is appropriate for the subject to participate in the
study;

- Being positive for human immunodeficiency virus or hepatitis B or C;

- History of surgical procedure for weight loss at any time (e.g. gastroplasty, gastric
bypass, gastrectomy or partial gastrectomy, adjustable banding, gastric sleeve);

- Being a smoker or having been a smoker in the previous 6 months;

- Abnormal eating patterns identified by registered dietitian interview (dietary
fat<15%, dietary fat>45%, dietary protein >30%);

- Working night shifts;

- Night eating syndrome (at least 25% of food intake is consumed after the evening meal
and/or at least two episodes of nocturnal eating per week);

- Traveling > 2 time zones 2 weeks prior to an inpatient CTRC study visit;

- Currently participating in any formal weight loss or physical activity programs or
clinical trials.