PURPOSE: Prediabetes and future risk of type 2 diabetes are significant issues in obese adolescents, especially Latinos. We previously noted few significant group effects induced by a 16-week high-fiber low-sugar nutrition education program plus twice/week strength training (N+ST). In this study, we analyzed white blood cell transcriptional profiles and explore whether underlying genetic networks relate to measured phenotypes. Specifically, we hypothesized that intervention-related gene expression changes might predict phenotypic changes. METHODS: We isolated mRNA from pre- and post-intervention blood cells and used transcriptional profiling via Illumina's HumanRef-8 v2 Expression BeadChip (Controls (C): n=15, N+ST: n=12). To determine the genes' functional grouping, we ran Ingenuity Pathway Analysis on N+ST group's significantly-changed probes (p1.41, unchanged in C). RESULTS: We found 4 significant Canonical Pathways N+ST (p<0.01). We further investigated one pathway most a priori related to the available phenotypic measures, insulin receptor signaling (p=.0015). We derived 9 genes for further analysis: ACLY, CBL, CRKL, FOXO3, FOXO4, JAK1, MTOR, PIK3R2, and TSC1, and correlated their change to the change in 14 measures of body composition, glucose regulation and insulin sensitivity. We found a direct relationship (p<0.05), except for FOX03, between the increase in their mRNA level and hepatic fat fraction (HFF) decrease; TSC1, CRLK, ACLY, and MTOR, remained significant after Bonferonni correction (two-tailed p<0.0004). CONCLUSIONS: HFF is a marker of non-alcoholic fatty liver disease and an important risk factor for metabolic dysfunction. We demonstrate that in the N+ST group, there is mRNA upregulation in the insulin receptor signaling pathway in white blood cells, related to a decrease in HFF. A N+ST intervention is potentially efficacious for reducing risk for non-alcoholic fatty liver disease and its related metabolic complications in Latino adolescents.