BackgroundThe TALLYHO/Jng (TH) mouse is a polygenic model for obesity and type 2 diabetes first described in the literature in 2001. The origin of the TH strain is an outbred colony of the Theiler Original strain and mice derived from this source were selectively bred for male hyperglycemia establishing an inbred strain at The Jackson Laboratory. TH mice manifest many of the disease phenotypes observed in human obesity and type 2 diabetes.ResultsWe sequenced the whole genome of TH mice maintained at Marshall University to a depth of approximately 64.8X coverage using data from three next generation sequencing runs. Genome-wide, we found approximately 4.31 million homozygous single nucleotide polymorphisms (SNPs) and 1.10 million homozygous small insertions and deletions (indels) of which 98,899 SNPs and 163,720 indels were unique to the TH strain compared to 28 previously sequenced inbred mouse strains. In order to identify potentially clinically-relevant genes, we intersected our list of SNP and indel variants with human orthologous genes in which variants were associated in GWAS studies with obesity, diabetes, and metabolic syndrome, and with genes previously shown to confer a monogenic obesity phenotype in humans, and found several candidate variants that could be functionally tested using TH mice. Further, we filtered our list of variants to those occurring in an obesity quantitative trait locus, tabw2, identified in TH mice and found a missense polymorphism in the Cidec gene and characterized this variant’s effect on protein function.ConclusionsWe generated a complete catalog of variants in TH mice using the data from whole genome sequencing. Our findings will facilitate the identification of causal variants that underlie metabolic diseases in TH mice and will enable identification of candidate susceptibility genes for complex human obesity and type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3245-6) contains supplementary material, which is available to authorized users.

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The co-epidemic of obesity and type 2 diabetes is associated with increased morbidity and mortality. Genetic factors are highly involved in the development of these diseases, in the form of interactions of multiple genes within obesogenic and diabetogenic environments, such as a high fat diet. The TALLYHO/Jng (TH) mouse is an inbred polygenic model for human obesity and type 2 diabetes. In order to further develop the TH mouse as a clinically relevant model, we investigated diet dependence of obesity and type 2 diabetes in TH mice vs. C57BL/6 (B6) mice. TH and B6 mice were weaned onto a standard rodent chow, semi-purified high-sucrose low-fat (HSLF), or semi-purified high-sucrose high-fat (HSHF) diet and maintained on these diets throughout the study. Despite similar fat contents in HSLF diets and chow, both B6 and TH mice responded to HSLF diets, with increases in adiposity. TH mice, but not B6 mice, exhibited significantly higher adiposity with severely aggravated glucose intolerance and hyperglycemia on HSHF diets compared to the other diets. HSLF diets also advanced diabetes in TH mice compared to chow, but it did not surpass the effects of HSHF diets. The severe glucose intolerance and hyperglycemia in TH mice on both HSLF and HSHF diets were accompanied by significantly reduced mRNA levels compared to B6 mice. The present data demonstrate that diets are important modulators of genetic susceptibility to type 2 diabetes and obesity in TH mice. The interplay between heredity and dietary environment in TH mice appears to amplify insulin resistance, contributing to severe glucose intolerance and diabetes.

The TALLYHO (TH) mouse presents a metabolic syndrome of obesity, type 2 diabetes, and hyperlipidemia. Highly significant quantitative trait loci (QTLs) linked to adiposity (proximal) and hypercholesterolemia (distal) were previously identified on chromosome (Chr) 1 in a genome-wide scan of F2 mice from C57BL/6J (B6)×TH. In this study we generated congenic mouse strains that carry the Chr 1 QTLs derived from TH on a B6 background; B6.TH-Chr1-128Mb (128 Mb in size) and B6.TH-Chr1-92Mb (92 Mb in size, proximally overlapping). We characterized these congenic mice on chow and high fat (HF) diets. On chow, B6.TH-Chr1-128Mb congenic mice exhibited a slightly larger body fat mass compared with B6.TH-Chr1-92Mb congenic and B6 mice, while body fat mass between B6.TH-Chr1-92Mb congenic and B6 mice was comparable. Plasma total cholesterol levels were significantly higher in B6.TH-Chr1-128Mb congenics compared to B6.TH-Chr1-92Mb congenic and B6 mice. Again, there was no difference in plasma total cholesterol levels between B6.TH-Chr1-92Mb congenic and B6 mice. All animals gained more body fat and exhibited higher plasma total cholesterol levels when fed HF diets than fed chow, but these increases were greater in B6.TH-Chr1-128Mb congenics than in B6.TH-Chr1-92Mb congenic and B6 mice. These results confirmed the effect of the 128Mb TH segment from Chr 1 on body fat and plasma cholesterol values and showed that the distal segment of Chr 1 from TH is necessary to cause both phenotypes. Through bioinformatic approaches we generated a list of potential candidate genes within the distal region of Chr 1 and tested Ifi202b and Apoa2. We conclude that Chr 1 QTLs largely confer obesity and hypercholesterolemia in TH mice and can be promising targets for identifying susceptibility genes. Congenic mouse strains will be a valuable resource for gene identification.

In the midst of the ongoing obesity epidemic, brown adipose tissue (BAT) has emerged as a potential therapeutic target. BAT is a thermogenic organ in mammals that is characterized by adipocytes with numerous mitochondria. BAT uses cellular free fatty acids derived from the lipolysis of triglyceride droplets to generate heat via the action of uncoupling protein 1 (Ucp1), located in the inner mitochondrial membrane. In this study, we analyzed mRNA and protein levels of Ucp1 and genes related to inflammation, mitochondrial biogenesis, and lipolysis in BAT of the TALLYHO/JngJ (TH) mouse, a polygenic model of obesity and type 2 diabetes. At four weeks of age, TH and C57BL/6J (B6) mice were weaned onto chow or high fat (HF) diets. At twenty weeks of age, mice were killed, and interscapular BAT was collected. BAT of TH mice appeared discolored and larger than that of B6. mRNA and protein levels in BAT were measured using qPCR and western blot analysis, respectively. There were no significant differences in Ucp1 mRNA levels between TH and B6 mice on either diet. Inflammatory marker interleukin 6 (IL6) mRNA levels were significantly increased in TH mice on HF diets compared to other groups. Interestingly, HF diets increased adipose triglyceride lipase (ATGL) mRNA levels in B6 mice, but not in TH. In summary, we observed genotype-dependent responses to HF diets for IL6 and ATGL expressions in BAT of TH and B6 mice. These results may signify increased inflammation and reduced lipolysis in BAT during the development of obesity.