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

• Published in: Nutrition research (New York, N.Y.) N.Y.), 2024-11, Vol.133, p.78
• Main Authors: Sweet, Michael G., Iglesias-Carres, Lisard, Ellsworth, Peter N., Carter, Jared D., Nielsen, Dahlia M., Aylor, David L., Tessem, Jeffery S., Neilson, Andrew P.
• Format: Article
• Language: English
• Subjects: Diversity Outbred; EGCG; gene x environment; genetic polymorphism; phenotype
• ISSN: 0271-5317; 1879-0739; 1879-0739
• DOI: 10.1016/j.nutres.2024.11.008

•Diversity Outbred (DO) mice presented extreme obese phenotype variation•Mice on a high-fat diet had 6.5-38.1% body fat•When (−)-epigallocatechin gallate (EGCG) was added, mice had 7.6-42.6% body fat•When EGCG was added, 11/50 mice lost fat•Great variation in obesity and EGCG effects in DO mice vs. studies in inbred mice•Large genotyping studies may identify genetic loci controlling response to EGCG 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 N=50 DO mice. Mice 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 (4.0-13.9% 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. We conducted a longitudinal phenotyping study in Diversity Outbred mice. Mice were fed a high fat diet, then high-fat diet + 0.3% (−)-epigallocatechin gallate (EGCG). All mice gained body fat on the high-fat diet; 11/50 mice lost body fat when EGCG was introduced. Variability in obesity biomarkers was greater than for inbred strains. Diversity Outbred mice represent a model of genetic and phenotypic variability that can be used to explore precision nutrition applications