Genetic characterization of the hypertriglyceridemia and the related traits in obese diabetic TALLYHO/JngJ mice

Type 2 diabetes mellitus (T2DM) is the most common form of human diabetes, accounting for approximately 90% of cases and often coexists with obesity. Elevated triglyceride levels and small dense low density lipoprotein particles and reduced high density lipoprotein cholesterol constitute diabetic dyslipidemia. Diabetic patients often develop hypertriglyceridemia (HTG) at the early stage of the disease, before the onset of overt hyperglycemia (diabetes). It is well-established that genetic factors significantly influence the onset of HTG, yet no susceptibility genes for common forms of HTG have been identified in human populations to date. TALLYHO/JngJ (TH) mice are a newly established inbred polygenic model for obesity and T2DM. These mice are characterized by insulin resistance, hyperinsulinemia, diabetes (males), obesity, and dyslipidemia. TH male mice rapidly develop HTG at a very young age before the onset of overt diabetes, and this HTG is accompanied by hyperinsulinemia, and precedes glucose intolerance. Accordingly, we hypothesize that the HTG may become a strong risk factor for overt diabetes in these mice and TH allelic differences at the underlying genetic susceptibility loci confer predisposition to HTG in TH mice. In an attempt to test these hypotheses, the aim of this study is to establish the genomic location(s) linked to the HTG in TH mice. In order to achieve this aim, we generated F2 mice from an intercross of F1[C57BL/6J (B6) x TH] mice. The F2 mice were then phenotyped for HTG and related traits including hypercholemia, hyperglycemia, and obesity. F2 mice were also genotyped with simple sequence repeat markers over the entire genome. Statistical analysis to detect significant loci that co- segregate with the traits was conducted using quantitative trait loci (QTLs) mapping. We found significant QTLs linked to HTG on chromosomes 1 and 8. Chromosome 1 QTL was also associated with hypercholesterolemia. A significant QTL responsible for fat pad weights was detected on chromosome 1 located proximal to the HTG QTL. A QTL on chromosome 4 was significantly linked to hyperglycemia. For all these traits, mice homozygous for TH alleles exhibited higher values than mice heterozygous or homozygous for B6 alleles. In summary, our genetic study revealed a complex pattern of inheritance and mapped significant QTLs for HTG and related traits in TH mice. Identifying the genes for these QTLs will enhance our understanding of diabetic HTG, and provide new targets to prevent it