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Objectives The TALLYHO (TH) mouse is a polygenic model for obesity, type 2 diabetes and hyperlipidemia. We previously established a subcongenic mouse with TH donor segment, ∼25 Mb, on chromosome (Chr) 1 in a C57BL/6J (B6) background that harbors quantitative trait loci (QTL) conferring hypercholesterolemia, named Tchol1 (Tallyho Associated Cholesterol 1). The subcongenic mouse developed hypercholesterolemia compared to B6 mice demonstrating that distal segment of Chr 1 from TH genome is necessary to cause the hypercholesterolemia. In this study, we tested the candidacy of the apolipoprotein A2 (Apoa2) gene for Tachol1 by the quantitative complementation test. Apoa2, known regulator of cholesterol metabolism, maps to the Tchol1 locus. Methods To carry out the quantitative complementation test, both TH-homozygous Tachol1 subcongenic and B6-homozygous (B6) mice were mated to the Apoa2 knockout heterozygous [wild-type (wt)/null] mice to produce four types of animals; TH/wt, TH/null, B6/wt, and B6/null. Both male and female mice were weaned onto standard rodent chow and maintained. Blood was collected when animals were euthanized at 16 weeks of age. Total plasma cholesterol levels were determined using colorimetric assays. A two-way ANOVA was used to evaluate Apoa2 (null vs. wt) and Tachol1 (TH vs. B6) interaction effects for dependent variables, followed by the multiple comparison post test with Tukey correction using GraphPad Prism 8. Results Total plasma cholesterol levels were: 137 ± 5 (TH/wt), 119 ± 8 (TH/null), 103 ± 8 (B6/wt), and 80 ± 4 (B6/null) for males, and 149 ± 8 (TH/wt), 130 ± 9 (TH/null), 98 ± 3 (B6/wt), and 103 ± 6 (B6/null) for females [mean ± s.e.m; mg/dl]. Two-way ANOVA revealed no significant interaction between Tchol1 and Apoa2 knockout alleles for total plasma cholesterol levels in both males and females. However, there were significant main effects of Tchol1 and Apoa2 knockout alleles on total plasma cholesterol levels in males, while significant main effects of Tchol1 on them in females. Conclusions No significant interaction effect between knockout and QTL alleles is interpreted as evidence that the knockout locus is not equal to the QTL. Our results suggest that the Apoa2 gene is not identical to the Tchol1 QTL. Funding Sources AHA 18AIREA33960437, NIH 1 R15 DK113604-01A1, the WV-INBRE grant (P20GM103434), and the COBRE ACCORD grant (1P20GM121299).

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.