Gene expression profiles of a mouse congenic strain carrying an obesity susceptibility QTL under obesigenic diets

Abstract

Genetic factors are strongly involved in the development of obesity, likely through the interactions of susceptibility genes with obesigenic environments, such as high-fat, high-sucrose (HFS) diets. Previously, we have established a mouse congenic strain on C57BL/6 J background, carrying an obesity quantitative trait locus (QTL), tabw2, derived from obese diabetic TALLYHO/JngJ mice. The tabw2 congenic mice exhibit increased adiposity and hyperleptinemia, which becomes exacerbated upon feeding HFS diets. In this study, we conducted genome-wide gene expression profiling to evaluate differentially expressed genes between tabw2 and control mice fed HFS diets, which may lead to identification of candidate genes as well as insights into the mechanisms underlying obesity mediated by tabw2. Both tabw2 congenic mice and control mice were fed HFS diets for 10 weeks beginning at 4 weeks of age, and total RNA was isolated from liver and adipose tissue. Whole-genome microarray analysis was performed and verified by real-time quantitative RT-PCR. At False Discovery Rate adjusted P < 0.05, 1026 genes were up-regulated and 308 down-regulated in liver, whereas 393 were up-regulated and 187 down-regulated in adipose tissue in tabw2 congenic mice compared to controls. Within the tabw2 QTL interval, 70 genes exhibited differential expression in either liver or adipose tissue. A comprehensive pathway analysis revealed a number of biological pathways that may be perturbed in the diet-induced obesity mediated by tabw2.

Fig. 1

Construction of a congenic mouse strain carrying the obesity QTL on chromosome 6, named tabw2, derived from TALLYHO/JngJ (TH) mice in the C57BL/6J (B6) background by marker assisted backcrossing. An obese TH male mouse was crossed to a normal B6 female mouse, and the resultant F1 (or N1) mice were backcrossed to B6. Heterozygotes for the QTL were selected using flanking markers (shown as dotted line) and backcrossed again to B6. This procedure was repeated for 10 cycles of backcrossing at which point two heterozygotes were intercrossed to yield offspring that are homozygous for the TH alleles (tabw2 mice) and for the B6 alleles (control mice) across the congenic region

Fig. 2

Volcano plot comparison of gene expression between control (B) and tabw2 (T) mice in liver and adipose tissue. The X-axis indicates the differential expression, plotting the fold-difference ratios on a log-2 scale. The Y-axis indicates log10 statistical significance levels for difference in expression. Vertical reference lines indicate 2-fold expression change, and a horizontal reference line is drawn at P < 0.05