Phenotype variability in diet-induced obesity and response to (-)-epigallocatechin gallate supplementation in a Diversity Outbred mouse cohort: A model for exploring gene x diet interactions for dietary bioactives

The flavan-3-ol (-)-epigallocatechin gallate (EGCG) blunts obesity in inbred mice, but human clinical trials have yielded mixed results. Genetic homogeneity in preclinical models may explain translational disconnect between rodents and humans. The Diversity Outbred (DO) mouse model provides genotype and phenotype variability for characterization of gene x environment (i.e., diet) interactions. We conducted a longitudinal phenotyping study in DO mice. Mice (n = 50) were fed a high-fat diet for 8 weeks and then a high-fat diet + 0.3% EGCG for 8 weeks. We hypothesized that obesity and any protective effects of EGCG would exhibit extreme variability in these genetically heterogeneous mice. As anticipated, DO mice exhibited extreme variation in body composition at baseline (4%-13.9% fat), after 8 weeks of high-fat diet (6.5%-38.1% fat), and after 8 weeks of high-fat diet + EGCG (7.6%-42.6% fat), greater than what is observed in inbred mice. All 50 mice gained body fat on the high-fat diet (changes from baseline of +5% ± 640%). Intriguingly, adiposity variability increased when EGCG was added to the diet (changes from the high-fat diet alone of -52% ± 390%), with 11/50 mice losing body fat. We postulate that the explanation for this variability is genetic heterogeneity. Our data confirm the promise for EGCG to manage obesity but suggest that genetic factors may exert significant control over the efficacy of EGCG. Larger studies in DO mice are needed for quantitative trait loci mapping to identify genetic loci governing EGCG x obesity interactions and translate these findings to precision nutrition in humans.