To more effectively address the problem of weight regain following weight loss for obese individuals, this study will evaluate the underlying biology of the reduced obese state. In depth studies of appetite, energy expenditure, physical activity levels and fat metabolism will be completed in obese and reduced obese individuals; with the latter subdivided into those who have lost weight with diet alone or diet plus exercise. Individuals will be studied following a brief overfeeding period to better understand how differences in biological responses to overeating might be involved in promoting or protecting against weight gain.

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.