Obesity resistant mechanisms in the Lean polygenic mouse model as indicated by liver transcriptome and expression of selected genes in skeletal muscle

<p>Abstract</p> <p>Background</p> <p>Divergently selected Lean and Fat mouse lines represent unique models for a polygenic form of resistance and susceptibility to obesity development. Previous research on these lines focused mainly on obesity-susceptible factors in the Fat line. This study aimed to examine the molecular basis of obesity-resistant mechanisms in the Lean line by analyzing various fat depots and organs, the liver transcriptome of selected metabolic pathways, plasma and lipid homeostasis and expression of selected skeletal muscle genes.</p> <p>Results</p> <p>Expression profiling using our custom Steroltalk v2 microarray demonstrated that Lean mice exhibit a higher hepatic expression of cholesterol biosynthesis genes compared to the Fat line, although this was not reflected in elevation of total plasma or liver cholesterol. However, FPLC analysis showed that protective HDL cholesterol was elevated in Lean mice. A significant difference between the strains was also found in bile acid metabolism. Lean mice had a higher expression of <it>Cyp8b1</it>, a regulatory enzyme of bile acid synthesis, and the <it>Abcb11 </it>bile acid transporter gene responsible for export of acids to the bile. Additionally, a higher content of blood circulating bile acids was observed in Lean mice. Elevated HDL and upregulation of some bile acids synthesis and transport genes suggests enhanced reverse cholesterol transport in the Lean line - the flux of cholesterol out of the body is higher which is compensated by upregulation of endogenous cholesterol biosynthesis. Increased skeletal muscle <it>Il6 </it>and <it>Dio2 </it>mRNA levels as well as increased activity of muscle succinic acid dehydrogenase (SDH) in the Lean mice demonstrates for the first time that changes in muscle energy metabolism play important role in the Lean line phenotype determination and corroborate our previous findings of increased physical activity and thermogenesis in this line. Finally, differential expression of <it>Abcb11 </it>and <it>Dio2 </it>identifies novel strong positional candidate genes as they map within the quantitative trait loci (QTL) regions detected previously in crosses between the Lean and Fat mice.</p> <p>Conclusion</p> <p>We identified novel candidate molecular targets and metabolic changes which can at least in part explain resistance to obesity development in the Lean line. The major difference between the Lean and Fat mice was in increased liver cholesterol biosynthesis gene mRNA expression, bile acid metabolism and changes in selected muscle genes' expression in the Lean line. The liver <it>Abcb11 </it>and muscle <it>Dio2 </it>were identified as novel positional candidate genes to explain part of the phenotypic difference between the Lean and Fat lines.</p

Congenic and bioinformatics analyses resolved a major-effect Fob3b QTL on mouse Chr 15 into two closely linked loci.

We previously identified a Chr 15 quantitative trait locus (QTL) Fob3b in lines of mice selected for high (Fat line) and low (Lean line) body fat content that represent a unique model of polygenic obesity. Here we genetically dissected the Fob3b interval by analyzing the phenotypes of eight overlapping congenic lines and four F(2) congenic intercrosses and prioritized candidates by bioinformatics approaches. Analyses revealed that the Fob3b QTL consists of at least two separate linked QTLs Fob3b1 and Fob3b2. They exhibit additive inheritance and are linked in coupling with alleles originating from the Lean line, decreasing obesity-related traits. In further analyses, we focused on Fob3b1 because it had a larger effect on obesity-related traits than Fob3b2, e.g., the difference between homozygotes for adiposity index (ADI) percentage was 1.22 and 0.77% for Fob3b1 and Fob3b2, respectively. A set of bioinformatics tools was used to narrow down positional candidates from 85 to 4 high-priority Fob3b1 candidates. A previous single Fob3b QTL was therefore resolved into another two closely linked QTLs, confirming the fractal nature of QTLs mapped at low resolution. The interval of the original Fob3b QTL was narrowed from 22.39 to 4.98 Mbp for Fob3b1 and to 7.68 Mbp for Fob3b2, which excluded the previously assigned candidate squalene epoxidase (Sqle) as the causal gene because it maps proximal to refined Fob3b1 and Fob3b2 intervals. A high-resolution map along with prioritization of Fob3b1 candidates by bioinformatics represents an important step forward to final identification of the Chr 15 obesity QTL

Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness

The discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge. We used the polygenic \u27lean\u27 mouse model, which has been selected for low adiposity over 60 generations, to identify mitochondrial thiosulfate sulfurtransferase (Tst; also known as rhodanese) as a candidate obesity-resistance gene with selectively increased expression in adipocytes. Elevated adipose Tst expression correlated with indices of metabolic health across diverse mouse strains. Transgenic overexpression of Tst in adipocytes protected mice from diet-induced obesity and insulin-resistant diabetes. Tst-deficient mice showed markedly exacerbated diabetes, whereas pharmacological activation of TST ameliorated diabetes in mice. Mechanistically, TST selectively augmented mitochondrial function combined with degradation of reactive oxygen species and sulfide. In humans, TST mRNA expression in adipose tissue correlated positively with insulin sensitivity in adipose tissue and negatively with fat mass. Thus, the genetic identification of Tst as a beneficial regulator of adipocyte mitochondrial function may have therapeutic significance for individuals with type 2 diabetes. Nat Med 2016 Jul; 22(7):771-9