Hepatic gene expression variations in response to high-fat diet-induced impaired glucose tolerance using RNAseq analysis in collaborative cross mouse population

Abstract

Hepatic gene expression is known to differ between healthy and type 2 diabetes conditions. Identifying these variations will provide better knowledge to the development of gene-targeted therapies. The aim of this study is to assess diet-induced hepatic gene expression of susceptible versus resistant CC lines to T2D development. Next-generation RNA-sequencing was performed for 84 livers of diabetic and non-diabetic mice of 41 different CC lines (both sexes) following 12 weeks on high-fat diet (42% fat). Data analysis revealed significant variations of hepatic gene expression in diabetic versus non-diabetic mice with significant sex effect, where 601 genes were differentially expressed (DE) in overall population (males and females), 718 genes in female mice, and 599 genes in male mice. Top prioritized DE candidate genes were Lepr, Ins2, Mb, Ckm, Mrap2, and Ckmt2 for the overall population; for females-only group were Hdc, Serpina12, Socs1, Socs2, and Mb, while for males-only group were Serpine1, Mb, Ren1, Slc4a1, and Atp2a1. Data analysis for sex differences revealed 193 DE genes in health (Top: Lepr, Cav1, Socs2, Abcg2, and Col5a3), and 389 genes DE between diabetic females versus males (Top: Lepr, Clps, Ins2, Cav1, and Mrap2). Furthermore, integrating gene expression results with previously published QTL, we identified significant variants mapped at chromosomes at positions 36-49 Mb, 62-71 Mb, and 79-99 Mb, on chromosomes 9, 11, and 12, respectively. Our findings emphasize the complexity of T2D development and that significantly controlled by host complex genetic factors. As well, we demonstrate the significant sex differences between males and females during health and increasing to extent levels during disease/diabetes. Altogether, opening the venue for further studies targets the discovery of effective sex-specific and personalized preventions and therapies.

Deletion of NoxO1 limits atherosclerosis development in female mice

“…Nox4 was shown to be downregulated in females. Another liver specific study of Abu-Toamih confirmed downregulation of Nox4 in females [ 37 ] ( Table 1 ). This study additionally described higher Lepr expression in female mice.…”

“…To validate the data regarding gender differences we examined two studies about gender differences in hepatic tissue. A study of Lau-Corona et al comparing gender specific effects in liver tissue [ 36 , 37 ] showed sex specific differences in glutathion-S-transferases, Nox2 and Nox4 ( Table 1 ). Nox4 was shown to be downregulated in females.…”

Studying host genetic background effects on multimorbidity of intestinal cancer development, type 2 diabetes and obesity in response to oral bacterial infection and high‐fat diet using the collaborative cross (CC) lines

“…In our study, the CC lines exhibited tremendous variation in glucose sensibility, body weight gain and polyp counts. We believe that by using this genetic reference population and expanding the number of the lines studied to 30 or more and using genome‐wide association studies (GWAS), we will be able to identify modifier genes associated with the multimorbidity of these diseases , as was successfully achieved in our previous studies 12,14‐20,22,34‐36 …”

Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model

“…The sex bias of hepatic gene expression has also been described in several inbred mouse strains [8,10,55]. Underlying mechanisms for genetically-based differences between strains are poorly understood [49,[56][57][58][59], primarily because most studies of sex bias in mouse liver have focused on strains of primarily M. m. domesticus genetic background (i.e., CD-1 and C57BL/ 6J) and did not include wild-derived strains.…”