One-Week Elderberry Juice Intervention Promotes Metabolic Flexibility in the Transcriptome of Overweight Adults During a Meal Challenge

Background: Metabolic flexibility, the ability to efficiently switch between fuel sources in response to changing nutrient availability and energy demands, is recognized as a key determinant of metabolic health. In a recent randomized controlled human feeding trial, overweight individuals receiving American black elderberry juice (EBJ) demonstrated improvements in multiple clinical indices of metabolic flexibility, but the mechanisms of action were unexplored. The objective of this study was to utilize RNA sequencing to examine how EBJ modulates the transcriptional response to fasting and feeding, focusing on pathways related to metabolic flexibility. Methods: Overweight or obese adults (BMI > 25 kg/m2) without chronic illnesses were randomized to a 5-week crossover study protocol with two 1-week periods of twice-daily EBJ or placebo (PL) separated by a washout period. RNA sequencing was performed on peripheral blood mononuclear cells from 10 participants to assess transcriptomic responses collected at fasting (pre-meal) and postprandial (120 min post-meal) states during a meal-challenge test. Results: The fasted-to-fed transition for EBJ showed 234 differentially expressed genes following EBJ consumption compared to 59 genes following PL, with 44 genes shared between interventions. EBJ supplementation showed significantly higher enrichment of several metabolic pathways including insulin, FoxO, and PI3K–Akt signaling. KEGG pathway analysis showed 27 significant pathways related to metabolic flexibility compared to 7 for PL. Conclusions: Our findings indicate that short-term elderberry juice consumption may promote metabolic flexibility in overweight adults.