Experimental Approach to Test Predictions of Body Weight Regulation Models

The regulation of human body weight and fatness is not fully understood. Although some models of regulation have been proposed (set point, dual-intervention point, others), no studies have been designed to test their predictions. In this pilot and feasibility study, the investigators will implement an experimental approach to test the predictions of models of body weight regulation in humans. Men and women with either low body weight or obesity will be exposed to a 2-day fasting followed by a 2-day ad-libitum refeeding. During the entire fasting-refeeding period, energy intake and expenditure will be accurately measured within metabolic chambers. The investigators will therefore determine the compensatory responses to fasting elicited to prevent weight loss. The results will serve to design and power future studies to better understand body weight regulation.

Background:

Although body weight regulation models have been proposed, experimental approaches for testing their predictions are lacking. The set point (SP) model proposes that a biologically determined fatness is defended by activating compensatory responses to prevent its change. The dual-intervention point (DIP) model proposes that there are two levels of fatness (lower and upper intervention points) within which fatness is weakly regulated. Compensatory responses would only be activated once the lower or upper intervention points are reached. In response to prolonged fasting, the SP model predicts the compensatory responses to be independent of the initial body weight. In contrast, the DIP model predicts higher responses in individuals who are closer to the lower intervention point (low body weight) compared to those who are farther away (obesity). None of these models predicts a different response in men vs. women. Our pilot and feasibility study will implement an experimental approach to test these predictions in humans by thoroughly measuring compensatory responses in energy expenditure and energy intake.

Design:

Twelve individuals (3 men with low body weight and 3 with obesity; 3 women with low body weight and 3 with obesity) will be kept inpatient in metabolic chambers for 5 consecutive days and exposed to a 1-day energy balance, 2-day fasting, and 2-day ad-libitum refeeding. The primary outcome will be the extent of compensatory response, calculated as the cumulative energy balance during the 5-day inpatient period.

Objectives:

1. To determine the extent of compensatory response induced by a 2-day fasting followed by a 2-day ad-libitum refeeding in humans overall and among different subgroups (low body weight, obesity, men, women).
2. To explore the timing of the compensatory responses during a 2-day fasting followed by a 2-day ad-libitum refeeding in humans.
3. To explore potential physiological determinants of the inter-individual variability in the compensatory response induced by a 2-day fasting followed by a 2-day ad-libitum refeeding in humans.

Relevance:

Understanding how body weight is regulated in humans can help to prevent or treat obesity. In this pilot and feasibility study, the investigators propose an experimental approach to test the predictions of two body weight regulation models in response to fasting and explore potential sex differences. These preliminary data will be used to design and power future studies for testing models of body weight regulation in humans.

Eligibility Criteria:
Inclusion Criteria:

* Body mass index lower than 20 kg/m2 for the low body weight group, or 30 kg/m2 or greater for the obesity group
* 18-40 years old
* Nulliparous and regular menstrual cycle (25-35 days) during the last six months (in women)
* Normal thyroid function, blood count, and chemistry 15 panel (normal plasma glucose will be considered at \<100 mg/dL; normal serum HDL cholesterol at \>=50 mg/dL for women and \>=40 mg/dL for men; and normal serum triglycerides at \<150 mg/dL).
* Self-reported weight stability during the last six months (±3 kg)
* Rate the liking of at least one of the flavored liquid meals (Ensure Plus, Abbot Nutrition) between 5 and 8 on a 9-point Likert scale
* Willing to only drink up to two assigned flavors of Ensure Plus for two consecutive days

Exclusion Criteria:

* Eating disorders as indicated by a global score ≥2.80 in the Eating Disorder Examination Questionnaire, or a previous diagnosis of an eating disorder
* For the low body weight group, having food insecurity (with or without hunger) as assessed by the USDA
* Recreational moderate-intensity physical activity ≥150 min/week, recreational vigorous-intensity physical activity ≥75 min/week, or a combination of recreational moderate-intensity and vigorous-intensity physical activity (moderate time + \[2 × vigorous time\]) ≥150 min/week as assessed by the Global Physical Activity Questionnaire, or being a professional athlete
* Cigarette or vape smoking
* Intake of more than 14 alcoholic drinks per week
* Use of medications that may affect energy intake and/or expenditure, for example, semaglutide, liraglutide, exenatide, other GLP-1 receptor agonists, phentermine-topiramate, naltrexone-bupropion, orlistat, metformin, SGLT2 inhibitors, pramlintide, levocarnitine, amphetamines, and amphetamine-like drugs
* Human immunodeficiency virus, galactosemia, and lactose intolerance
* Diseases that affect energy homeostasis including endocrine such as hypo/hyperthyroidism, or type 1 or 2 diabetes; cancer; chronic pulmonary diseases; cardiovascular disease; and renal disease
* History of inflammatory bowel disease (ulcerative colitis, Crohn's), malabsorption syndromes (intestinal, pancreatic), and sprue or gluten intolerance
* Having moderate to severe sleep apnea defined as an oxygen desaturation index \&gt;10 times/hour assessed by overnight oximetry to be conducted on the night following the screening visit
* Use of oral hormonal contraceptives or less than 6 months using a hormonal intrauterine device (in women)
* Adults who are unable to consent
* Prisoners
* Currently pregnant or breastfeeding (in women)