Refeeding After Prolonged Fasting Triggers BCAA Drop and FGF21 Surge in Humans

Fasting-based interventions are attracting growing scientific and clinical interest as tools for metabolic rejuvenation, yet most human studies focus on the fasting phase itself and lack integrated hormonal and high-dimensional metabolomic data across both fasting and refeeding. This study from the University of Sydney addresses that gap with a comprehensive longitudinal metabolomics analysis.

Twenty adults (mean age 52 years, 55% women, mean BMI 28.8 kg/m²) spanning healthy, overweight, and obese cardiometabolic profiles underwent medically supervised water-only fasting averaging 9.8 days, followed by gradual plant-based refeeding for 5.3 days. Blood was drawn at three time points: baseline, end of fasting, and end of refeeding. Using mass spectrometry, investigators quantified 134 plasma metabolites spanning lipid, amino acid, and ketone pathways, alongside hormones including insulin, leptin, adiponectin, free T3, cortisol, and FGF21.

Fasting substantially remodeled the plasma metabolome. Free T3 fell significantly (p < 0.0001), reflecting a reduced metabolic rate. Seven metabolites previously linked to biological aging shifted markedly: glucose declined, 3-hydroxybutyric acid (a ketone body) rose, and amino acids glycine, glutamine, alanine, phenylalanine, and tyrosine all changed directionally consistent with ketogenic and gluconeogenic reprogramming. Counterintuitively, BCAAs (valine, leucine, isoleucine) remained stable throughout fasting despite the catabolic state, suggesting that peripheral tissues actively release BCAAs to sustain energy homeostasis and gluconeogenesis alongside ketogenesis. FGF21 levels did not rise during fasting in these human subjects—a notable contrast to rodent models where FGF21 is elevated during starvation.

Upon refeeding, the metabolome largely normalized (81% of metabolites returned toward baseline), but BCAAs declined sharply and significantly (valine −45%, leucine −52%, isoleucine −48%; all p < 0.001), consistent with insulin-stimulated uptake into skeletal muscle and other tissues. Simultaneously, FGF21 surged approximately fivefold—from 243 pg/mL to 1,176 pg/mL (p = 0.0007)—exclusively during the refeeding phase. The inverse association between falling BCAAs and rising FGF21 during refeeding points to a coordinated endocrine–metabolic response that may promote insulin sensitization and lipid oxidation as nutrients reenter circulation.

These findings carry meaningful implications for longevity and metabolic medicine. The refeeding phase emerges as a distinct and underappreciated therapeutic window during which key aging-related metabolites and hormones undergo dynamic remodeling. The human-specific timing of FGF21 elevation during refeeding—rather than fasting—suggests that translating rodent fasting biology to humans requires caution, and that dietary composition and timing of refeeding may be as important as the fast itself for optimizing metabolic outcomes.