Increased levels of plasma cysteine are associated with obesity and metabolic disturbances. Our recent genetic analyses in spontaneously hypertensive rats (SHR) revealed a mutated Folr1 (folate receptor 1) as the quantitative trait gene associated with diminished renal Folr1 expression, lower plasma folate levels, hypercysteinemia, hyperhomocysteinemia and metabolic disturbances. To further analyse the effects of the Folr1 gene expression on folate metabolism, we used mass spectrometry to quantify folate profiles in the plasma and liver of an SHR-1 congenic strain, with wild type Folr1 allele on the SHR genetic background, and compared them with the SHR strain. In the plasma, concentration of 5-methyltetrahydrofolate (5mTHF) was significantly higher in SHR-1 congenic rats compared to SHR (60+/-6 vs. 42+/-2 nmol/l, P<0.01) and 5mTHF monoglutamate was the predominant form in both strains (>99 % of total folate). In the liver, SHR-1 congenic rats showed a significantly increased level of 5mTHF and decreased concentrations of dihydrofolate (DHF), tetrahydrofolate (THF) and formyl-THF when compared to the SHR strain. We also analysed the extent of folate glutamylation in the liver. Compared with the SHR strain, congenic wild-type Folr1 rats had significantly higher levels of 5mTHF monoglutamate. On the other hand, 5mTHF penta- and hexaglutamates were significantly higher in SHR when compared to SHR-1 rats. This inverse relationship of rat hepatic folate polyglutamate chain length and folate sufficiency was also true for other folate species. These results strongly indicate that the whole body homeostasis of folates is substantially impaired in SHR rats compared to the SHR-1 congenic strain and might be contributing to the associated metabolic disturbances observed in our previous studies.

• MeSH
• Folate Receptor 1 genetics   MeSH
• Liver metabolism   MeSH
• Folic Acid blood   MeSH
• Folic Acid Deficiency blood   genetics   MeSH
• Rats, Inbred SHR genetics   MeSH
• Fatty Liver metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Metabolic syndrome is a highly prevalent human disease with substantial genomic and environmental components. Previous studies indicate the presence of significant genetic determinants of several features of metabolic syndrome on rat chromosome 16 (RNO16) and the syntenic regions of human genome. We derived the SHR.BN16 congenic strain by introgression of a limited RNO16 region from the Brown Norway congenic strain (BN-Lx) into the genomic background of the spontaneously hypertensive rat (SHR) strain. We compared the morphometric, metabolic, and hemodynamic profiles of adult male SHR and SHR.BN16 rats. We also compared in silico the DNA sequences for the differential segment in the BN-Lx and SHR parental strains. SHR.BN16 congenic rats had significantly lower weight, decreased concentrations of total triglycerides and cholesterol, and improved glucose tolerance compared with SHR rats. The concentrations of insulin, free fatty acids, and adiponectin were comparable between the two strains. SHR.BN16 rats had significantly lower systolic (18-28 mmHg difference) and diastolic (10-15 mmHg difference) blood pressure throughout the experiment (repeated-measures ANOVA, P < 0.001). The differential segment spans approximately 22 Mb of the telomeric part of the short arm of RNO16. The in silico analyses revealed over 1200 DNA variants between the BN-Lx and SHR genomes in the SHR.BN16 differential segment, 44 of which lead to missense mutations, and only eight of which (in Asb14, Il17rd, Itih1, Syt15, Ercc6, RGD1564958, Tmem161a, and Gatad2a genes) are predicted to be damaging to the protein product. Furthermore, a number of genes within the RNO16 differential segment associated with metabolic syndrome components in human studies showed polymorphisms between SHR and BN-Lx (including Lpl, Nrg3, Pbx4, Cilp2, and Stab1). Our novel congenic rat model demonstrates that a limited genomic region on RNO16 in the SHR significantly affects many of the features of metabolic syndrome.

• MeSH
• Genome MeSH
• Glucose Tolerance Test MeSH
• Hemodynamics MeSH
• Humans MeSH
• Chromosomes, Human, Pair 16 genetics   MeSH
• Metabolic Syndrome genetics   metabolism   physiopathology   MeSH
• Metabolome MeSH
• Rats, Inbred BN genetics   metabolism   physiology   MeSH
• Rats, Inbred SHR genetics   metabolism   physiology   MeSH
• Animals, Congenic genetics   metabolism   physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and accompanying metabolic disturbances. Recent advances in sequencing of genomes of BN-Lx and SHR progenitors of the BXH/HXB recombinant inbred (RI) strains as well as accumulation of multiple data sets of intermediary phenotypes in the RI strains, including mRNA and microRNA abundance, quantitative metabolomics, proteomics, methylomics or histone modifications, will make it possible to systematically search for genetic variants involved in regulation of gene expression and in the etiology of complex pathophysiological traits. New advances in manipulation of the rat genome, including efficient transgenesis and gene targeting, will enable in vivo functional analyses of selected candidate genes to identify QTL at the molecular level or to provide insight into mechanisms whereby targeted genes affect pathophysiological traits in the SHR.

• MeSH
• Species Specificity MeSH
• Insulin Resistance genetics   MeSH
• Rats MeSH
• Humans MeSH
• Quantitative Trait Loci genetics   MeSH
• Metabolic Syndrome classification   genetics   MeSH
• Rats, Inbred SHR classification   genetics   MeSH
• Rats, Transgenic genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Deficiency of fatty acid translocase Cd36 has been shown to have a major role in the pathogenesis of metabolic syndrome in the spontaneously hypertensive rat (SHR). We have tested the hypothesis that the effects of Cd36 mutation on the features of metabolic syndrome are contextually dependent on genomic background. We have derived two new congenic strains by introgression of limited chromosome 4 regions of SHR origin, both including the defective Cd36 gene, into the genetic background of a highly inbred model of insulin resistance and dyslipidemia, polydactylous (PD) rat strain. We subjected standard diet-fed adult males of PD and the congenic PD.SHR4 strains to metabolic, morphometric and transcriptomic profiling. We observed significantly improved glucose tolerance and lower fasting insulin levels in PD.SHR4 congenics than in PD. One of the PD.SHR4 strains showed lower triglyceride concentrations across major lipoprotein fractions combined with higher levels of low-density lipoprotein cholesterol compared with the PD progenitor. The hepatic transcriptome assessment revealed a network of genes differentially expressed between PD and PD.SHR4 with significant enrichment by members of the circadian rhythmicity pathway (Arntl (Bmal1), Clock, Nfil3, Per2 and Per3). In summary, the introduction of the chromosome 4 region of SHR origin including defective Cd36 into the PD genetic background resulted in disconnected shifts of metabolic profile along with distinct changes in hepatic transcriptome. The synthesis of the current results with those obtained in other Cd36-deficient strains indicates that the eventual metabolic effect of a deleterious mutation such as that of SHR-derived Cd36 is not absolute, but rather a function of complex interactions between environmental and genomic background, upon which it operates.

• MeSH
• CD36 Antigens genetics   metabolism   MeSH
• Genome MeSH
• Glucose genetics   metabolism   MeSH
• Glucose Tolerance Test MeSH
• Liver metabolism   MeSH
• Rats MeSH
• Models, Animal MeSH
• Rats, Inbred SHR genetics   MeSH
• Transcriptome MeSH
• Animals, Congenic genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• Keywords
• SHR, genetika esenciální hypertenze,
• MeSH
• Ankyrin Repeat genetics   MeSH
• Gene Expression genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Genotyping Techniques methods   MeSH
• Hypertension genetics   MeSH
• Disease Models, Animal MeSH
• Reverse Transcriptase Polymerase Chain Reaction utilization   MeSH
• Polymorphism, Genetic genetics   MeSH
• Rats, Inbred SHR genetics   MeSH
• Chromosomes, Mammalian genetics   MeSH
• Protein Splicing genetics   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH

The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and associated metabolic disturbances. Multiple quantitative trait loci associated with hemodynamic and metabolic parameters have been mapped in the SHR. Recently, it has become possible to identify some of the specific quantitative trait gene (QTG) variants that underlie quantitative trait loci linked to complex cardiovascular and metabolic traits in SHR related strains. Recombinant inbred strains derived from SHR and Brown Norway progenitors, together with SHR congenic and transgenic strains, have proven useful for establishing the identity of several QTGs in SHR models. It is anticipated that the combined use of linkage analyses and gene expression profiles, together with the recently available genome sequences of both the SHR and Brown Norway strains and new methods for manipulating the rat genome, will soon accelerate progress in identifying QTGs for complex traits in SHR-related strains.

• MeSH
• Gene Expression MeSH
• Rats, Inbred Strains genetics   MeSH
• Rats MeSH
• Quantitative Trait, Heritable MeSH
• Quantitative Trait Loci genetics   MeSH
• Chromosome Mapping MeSH
• DNA, Mitochondrial genetics   MeSH
• Rats, Inbred SHR genetics   MeSH
• Rats, Transgenic MeSH
• Gene Transfer Techniques MeSH
• Transposases MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH

The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and accompanying metabolic disturbances. In this model, the use of whole genome sequencing and gene expression profiling techniques, linkage and correlation analyses in recombinant inbred strains, and in vitro and in vivo functional studies in congenic and transgenic lines has recently enabled molecular identification of quantitative trait loci (QTLs) relevant to the metabolic syndrome: (1) a deletion variant in Cd36 (fatty acid translocase) responsible for QTLs on chromosome 4 associated with dyslipidemia, insulin resistance and hypertension, (2) mutated Srebf1 (sterol regulatory element binding factor 1) as a QTL on chromosome 10 influencing dietary-induced changes in hepatic cholesterol levels, and (3) Ogn (osteoglycin) as a QTL on chromosome 17 associated with left ventricular hypertrophy. In addition, selective replacement of the mitochondrial genome of the SHR with the mitochondrial genome of the Brown Norway rat influenced several major metabolic risk factors for type 2 diabetes and provided evidence that spontaneous variation in the mitochondrial genome per se can promote systemic metabolic disturbances relevant to the pathogenesis of metabolic syndrome. Owing to recent progress in the development of rat genomic resources, the pace of QTL identification and discovery of new disease mechanisms can be expected to accelerate in the near future.

• MeSH
• Genomics methods   MeSH
• Rats, Inbred Strains genetics   MeSH
• Rats MeSH
• Quantitative Trait Loci MeSH
• Metabolic Syndrome genetics   MeSH
• Disease Models, Animal MeSH
• Rats, Inbred SHR genetics   MeSH
• Gene Expression Profiling MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

Congenic strains are routinely used for positional mapping of quantitative trait loci; while conplastic strains, derived by substitution of different mitochondrial genomes on the same nuclear genetic background of inbred rodent strains, provide a way to unambiguously isolate effects of the mitochondrial genome on complex traits. Derivation of congenic or conplastic strains using a traditional backcross breeding strategy (10 backcrosses) takes more than 3 years. There are two principal strategies to speed up this process: (1) marker-assisted derivation of "speed" congenic/conplastic strains and (2) derivation of "supersonic" congenic/conplastic strains using in each backcross generation embryos obtained from 4-week-old superovulated females; thus, each backcross generation takes only 7 weeks. Both strategies could also be combined. In the current chapter, a method for derivation of "supersonic" congenic/conplastic rat strains is described.

• MeSH
• Genotype MeSH
• Rats, Inbred Strains genetics   MeSH
• Ovulation Induction methods   MeSH
• Rats MeSH
• Rats, Inbred BN genetics   MeSH
• Rats, Inbred SHR genetics   MeSH
• Embryo Transfer methods   MeSH
• Animals, Congenic genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

Recombinant inbred (RI) strains (Prague HXB/BXH set) represent a unique model that allows for permanent summation of genetic and physiological information as well as the study of age-dependent changes in phenotypes and/or gene regulation. This study compared blood pressure (BP) measured in adult animals of RI strains by radiotelemetry with BP values obtained in conscious rats of comparable age subjected to short-term carotid catheterization or with those obtained by direct carotid puncture under ether anesthesia (almost 20 years ago). After radiotelemetry recording, the contribution of major vasoactive systems to BP maintenance was studied by consecutive inhibition of the renin-angiotensin system (RAS), sympathetic nervous system (SNS), and nitric oxide synthase. We found highly significant interrelationships among baseline BP values obtained by radiotelemetry, carotid catheterization, or carotid puncture. This indicates considerable stability of RI strains over the course of their long existence, and confirms the reliability of BP values used for genetic studies performed in the past. Subsequent analysis of vasoactive system participation revealed the importance of SNS for the maintenance of BP, as determined by either radiotelemetry or catheterization. The BP of catheterized rats also correlated closely with acute captopril-induced BP changes, but this was not the case for rats measured by radiotelemetry. NO-dependent vasodilatation matched the BP effects of SNS and RAS in both measuring conditions. Residual BP (recorded at sodium nitroprusside-induced dilatation of resistance vessels) was also responsible for a significant portion of the BP variation in RI strains. Our study confirms the validity of RI strains for the further genetic and physiological research of hypertension.

• MeSH
• Antihypertensive Agents pharmacology   MeSH
• Financing, Organized MeSH
• Hypertension drug therapy   genetics   physiopathology   MeSH
• Rats, Inbred Strains genetics   MeSH
• Catheterization MeSH
• Blood Pressure genetics   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Monitoring, Physiologic MeSH
• Rats, Inbred SHR genetics   MeSH
• Recombinant Proteins genetics   MeSH
• Renin-Angiotensin System physiology   MeSH
• Heart Rate genetics   MeSH
• Sympathetic Nervous System physiology   MeSH
• Nitric Oxide Synthase metabolism   MeSH
• Telemetry MeSH
• Organ Size genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH

We have developed a new, double-congenic rat strain BN-Lx.SHR2, which carries two distinct segments of chromosome 2 introgressed from the spontaneously hypertensive rat strain (SHR) into the genetic background of congenic strain BN-Lx, which was previously shown to express variety of metabolic syndrome features. In 16-wk-old male rats of BN-Lx and BN-Lx.SHR2 strains, we compared their glucose tolerance and triacylglycerol and cholesterol concentrations in 20 lipoprotein subfractions and the lipoprotein particle sizes under conditions of feeding standard and high-sucrose diets. Introgression of two distinct SHR-derived chromosome 2 segments resulted in decreased adiposity together with aggravation of glucose intolerance in the double-congenic strain. The BN-Lx.SHR2 rats were more sensitive to sucrose-induced rise in triacylglycerolemia. Although the total cholesterol concentrations of the two strains were comparable after the standard diet and even lower in BN-Lx.SHR2 after sucrose feeding, detailed analysis revealed that under both dietary conditions, the double-congenic strain had significantly higher cholesterol concentrations in low-density lipoprotein fractions and lower high-density lipoprotein fractions. We established a new inbred model showing dyslipidemia and mild glucose intolerance without obesity, attributable to specific genomic regions. For the first time, the chromosome 2 segments of SHR origin are shown to influence other than blood pressure-related features of metabolic syndrome or to be involved in relevant nutrigenomic interactions.

• MeSH
• Cholesterol analysis   MeSH
• Financing, Organized MeSH
• Genomics MeSH
• Hypertension genetics   blood   pathology   MeSH
• Rats MeSH
• Lipoproteins chemistry   blood   MeSH
• Quantitative Trait Loci MeSH
• Disease Models, Animal MeSH
• Glucose Intolerance genetics   MeSH
• Rats, Inbred SHR genetics   MeSH
• Sucrose pharmacology   MeSH
• Chromosomes, Mammalian MeSH
• Triglycerides analysis   MeSH
• Adipose Tissue physiology   MeSH
• Animals, Congenic MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH