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

Simončič M, Režen T, Juvan P, Rozman D, Fazarinc G, Fievet C, Staels B, Horvat S - BMC Genomics (2011)

Bottom Line: A significant difference between the strains was also found in bile acid metabolism.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.The liver Abcb11 and muscle Dio2 were identified as novel positional candidate genes to explain part of the phenotypic difference between the Lean and Fat lines.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Ljubljana, Biotechnical Faculty, Department of Animal Science, Groblje 3, 1230 DomŽale, Slovenia.

ABSTRACT

Background: 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.

Results: 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 Cyp8b1, a regulatory enzyme of bile acid synthesis, and the Abcb11 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 Il6 and Dio2 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 Abcb11 and Dio2 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.

Conclusion: 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 Abcb11 and muscle Dio2 were identified as novel positional candidate genes to explain part of the phenotypic difference between the Lean and Fat lines.

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SDH-activity in m. gastrocnemius muscle tissue of the Lean and Fat mice. Striated muscle from regio cruris (m. gastrocnemius) was used to determine mitochondrial succinate dehydrogenase (SDH) activity levels. 12 of each Lean and Fat line mice were analysed and 150 muscle fibers per mouse were measured for densitometry. This histochemical assay demonstrated marked (*P < 0.001) increased level of SDH activity in muscle fibers of Lean mice suggesting pronounced increase in oxidative metabolism in this line. % densitometry with standard errors are displayed - lower transparency of muscle histological sections in the Lean mice resulted from higher SDH-enzyme activity which in turn gave lower % densitometry readings in the Lean line.
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Figure 5: SDH-activity in m. gastrocnemius muscle tissue of the Lean and Fat mice. Striated muscle from regio cruris (m. gastrocnemius) was used to determine mitochondrial succinate dehydrogenase (SDH) activity levels. 12 of each Lean and Fat line mice were analysed and 150 muscle fibers per mouse were measured for densitometry. This histochemical assay demonstrated marked (*P < 0.001) increased level of SDH activity in muscle fibers of Lean mice suggesting pronounced increase in oxidative metabolism in this line. % densitometry with standard errors are displayed - lower transparency of muscle histological sections in the Lean mice resulted from higher SDH-enzyme activity which in turn gave lower % densitometry readings in the Lean line.

Mentions: Analysis of m. gastrocnemius SDH-activity determined by histochemical reaction identified marked differences in oxidative capacity of skeletal muscle fibres from Fat versus Lean mice. Significantly higher levels of SDH activity were detected in muscle fibres of Lean mice (Figure 5, P < 0.001). Skeletal muscle interleukin 6 (Il6) mRNA level, a potent indicator of muscle physical activity, was examined using qRT-PCR. Lean mice muscle tissue displayed markedly elevated Il6 gene expression level (Table 2). Furthermore, a significant down- regulation of iodothyronine, type II deiodinase (Dio2) in m. gastrocnemius and m. quadriceps of Lean mice (Table 2) was determined.


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

Simončič M, Režen T, Juvan P, Rozman D, Fazarinc G, Fievet C, Staels B, Horvat S - BMC Genomics (2011)

SDH-activity in m. gastrocnemius muscle tissue of the Lean and Fat mice. Striated muscle from regio cruris (m. gastrocnemius) was used to determine mitochondrial succinate dehydrogenase (SDH) activity levels. 12 of each Lean and Fat line mice were analysed and 150 muscle fibers per mouse were measured for densitometry. This histochemical assay demonstrated marked (*P < 0.001) increased level of SDH activity in muscle fibers of Lean mice suggesting pronounced increase in oxidative metabolism in this line. % densitometry with standard errors are displayed - lower transparency of muscle histological sections in the Lean mice resulted from higher SDH-enzyme activity which in turn gave lower % densitometry readings in the Lean line.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3044672&req=5

Figure 5: SDH-activity in m. gastrocnemius muscle tissue of the Lean and Fat mice. Striated muscle from regio cruris (m. gastrocnemius) was used to determine mitochondrial succinate dehydrogenase (SDH) activity levels. 12 of each Lean and Fat line mice were analysed and 150 muscle fibers per mouse were measured for densitometry. This histochemical assay demonstrated marked (*P < 0.001) increased level of SDH activity in muscle fibers of Lean mice suggesting pronounced increase in oxidative metabolism in this line. % densitometry with standard errors are displayed - lower transparency of muscle histological sections in the Lean mice resulted from higher SDH-enzyme activity which in turn gave lower % densitometry readings in the Lean line.
Mentions: Analysis of m. gastrocnemius SDH-activity determined by histochemical reaction identified marked differences in oxidative capacity of skeletal muscle fibres from Fat versus Lean mice. Significantly higher levels of SDH activity were detected in muscle fibres of Lean mice (Figure 5, P < 0.001). Skeletal muscle interleukin 6 (Il6) mRNA level, a potent indicator of muscle physical activity, was examined using qRT-PCR. Lean mice muscle tissue displayed markedly elevated Il6 gene expression level (Table 2). Furthermore, a significant down- regulation of iodothyronine, type II deiodinase (Dio2) in m. gastrocnemius and m. quadriceps of Lean mice (Table 2) was determined.

Bottom Line: A significant difference between the strains was also found in bile acid metabolism.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.The liver Abcb11 and muscle Dio2 were identified as novel positional candidate genes to explain part of the phenotypic difference between the Lean and Fat lines.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Ljubljana, Biotechnical Faculty, Department of Animal Science, Groblje 3, 1230 DomŽale, Slovenia.

ABSTRACT

Background: 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.

Results: 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 Cyp8b1, a regulatory enzyme of bile acid synthesis, and the Abcb11 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 Il6 and Dio2 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 Abcb11 and Dio2 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.

Conclusion: 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 Abcb11 and muscle Dio2 were identified as novel positional candidate genes to explain part of the phenotypic difference between the Lean and Fat lines.

Show MeSH
Related in: MedlinePlus