Metabolic responses to 48 h fasting and refeeding in adults with and without obesity

Metabolic flexibility—the ability to adapt substrate utilization to availability—is commonly impaired in individuals with obesity. While short-term fasting promotes lipid utilization, it may lead to subsequent metabolic inflexibility by blunting carbohydrate metabolism upon refeeding. However, the extent to which this differs in obesity remains unknown. The aim of this study was to examine whether a 48 h fast differentially affects substrate utilization during refeeding in individuals with and without obesity. Adults classified as lean ( n = 16) or with obesity ( n = 16) (eight males and eight females per group) completed a 48 h fast followed by a mixed meal tolerance test (NCT05886738). Respiratory exchange ratio (RER), glucose, β-hydroxybutyrate (BHB), insulin, and free fatty acid (FFA) levels were measured at baseline, after 48 h of fasting, and 1 and 2 h postprandially to assess substrate utilization. Individuals with obesity exhibited baseline hyperinsulinemia despite similar glucose levels when compared to lean individuals. Fasting reduced circulating insulin and glucose, and elicited a shift toward fat oxidation in both groups, as reflected by decreased RER and elevated FFAs ( P < 0.001). Despite similar FFA concentrations, individuals with obesity demonstrated lower BHB concentrations ( P < 0.001) following the fast when compared to their lean counterparts. Upon refeeding, individuals with obesity demonstrated lower 2 h postprandial glucose excursions compared to lean participants ( P < 0.001). The presence of obesity may elicit a paradoxical advantage in restoring carbohydrate metabolism following short-term fasting. We speculate that fasting may alleviate basal hyperinsulinemia-induced insulin resistance, which partially counteracts fasting-induced glucose intolerance.