Metabolic Response to Extended Fasting in Humans with Normal Weight and Obesity: a Systematic Review

Background: Individuals with low body fat are closer to the lower intervention point defined in the dual-intervention model of body weight regulation. Therefore, their adaptive metabolic response to fasting could proceed to a greater extent than individuals with high body fat (obesity). We approached this hypothesis through a systematic review followed by weighted data analysis. Methods: PubMed was searched for reports measuring metabolic variables after an overnight and a prolonged fast (13-87 h) in adults with normal weight and obesity (PROSPERO registration #CRD42021278516). Nine reports were included (161 individuals). From weighted means and standard deviations, we assessed the effects of group (normal weight, obesity), time (overnight fast, 13 to 87 h fasting), and their interaction on metabolic variables. Results: Circulating ketone bodies and non-esterified fatty acids increased similarly in both groups during prolonged fasting. However, the increases reached higher values in normal-weight individuals after >60 h of fasting (interaction p < 0.05). Glycemia and respiratory quotient decreased similarly in both groups during fasting (time p < 0.001). Leptinemia and insulinemia were lower in individuals with normal weight, but the difference was progressively attenuated during fasting as individuals with obesity diminished their circulating concentrations (interaction p < 0.05). The counterregulatory hormones glucagon and cortisol showed similar responses to prolonged fasting in both groups. Resting metabolic rate (in kcal/ d) reached similar values in both groups after 48 h, but lower values were then observed in individuals with normal weight after 72 h (interaction p = 0.038). Conclusions: Prolonged fasting did not induce a consistent differential adaptive metabolic response between individuals with normal weight and obesity. Notably, a more robust increase in circulating lipid-related metabolites manifests over 60 h of fasting in individuals with normal weight. Prolonged fasting may appear insufficient to trigger different adaptive responses in individuals with a body fat content close to the lower intervention point. Other strategies may be needed to reveal the existence of such a model of body weight regulation.