Metabolic syndrome (MetS) is an important cause of worldwide morbidity and mortality. Its complex pathogenesis includes, on the one hand, sedentary lifestyle and high caloric intake, and, on the other hand, there is a clear genetic predisposition. PD (Polydactylous rat) is an animal model of hypertriglyceridemia, insulin resistance, and obesity. To unravel the genetic and pathophysiologic background of this phenotype, we compared morphometric and metabolic parameters as well as liver transcriptomes among PD, spontaneously hypertensive rat, and Brown Norway (BN) strains fed a high-fat diet (HFD). After 4 weeks of HFD, PD rats displayed marked hypertriglyceridemia but without the expected hepatic steatosis. Moreover, the PD strain showed significant weight gain, including increased weight of retroperitoneal and epididymal fat pads, and impaired glucose tolerance. In the liver transcriptome, we found 5480 differentially expressed genes, which were enriched for pathways involved in fatty acid beta and omega oxidation, glucocorticoid metabolism, oxidative stress, complement activation, triacylglycerol and lipid droplets synthesis, focal adhesion, prostaglandin synthesis, interferon signaling, and tricarboxylic acid cycle pathways. Interestingly, the PD strain, contrary to SHR and BN rats, did not express the Acsm3 (acyl-CoA synthetase medium-chain family member 3) gene in the liver. Together, these results suggest disturbances in fatty acid utilization as a molecular mechanism predisposing PD rats to hypertriglyceridemia and fat accumulation.

• Keywords
• Acsm3, high-fat diet, hypertriglyceridemia, insulin resistance, liver transcriptome, metabolic syndrome, polydactylous rat, spontaneously hypertensive rat,
• MeSH
• Diet, High-Fat adverse effects   MeSH
• Gene Expression MeSH
• Hypertriglyceridemia blood   genetics   MeSH
• Liver metabolism   MeSH
• Coenzyme A Ligases genetics   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Intra-Abdominal Fat metabolism   MeSH
• Polydactyly MeSH
• Rats, Inbred SHR MeSH
• Rats, Wistar MeSH
• Gene Expression Profiling methods   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acsm3 protein, rat MeSH Browser
• Coenzyme A Ligases MeSH

BACKGROUND: All-trans retinoic acid (ATRA, tretinoin) is a vitamin A derivative commonly used in the treatment of diverse conditions ranging from cancer to acne. In a fraction of predisposed individuals, the administration of ATRA is accompanied by variety of adverse metabolic effects, particularly by the induction of hyperlipidemia. We have previously derived a minimal congenic SHR.PD-(D8Rat42-D8Arb23)/Cub (SHR-Lx) strain sensitive to ATRA-induced increase of triacylglycerols and cholesterol under condition of high-sucrose diet. SHR-Lx differs only by 7 genes of polydactylous rat (PD/Cub) origin from its spontaneously hypertensive rat (SHR) progenitor strain. METHODS: Adult male rats of SHR and SHR-Lx strains were fed standard diet (STD) and experimental groups were subsequently treated with ATRA (15 mg/kg) via oral gavage for 16 days, while still on STD. We contrasted the metabolic profiles (including free fatty acids, triacylglycerols (TG) and cholesterol (C) in 20 lipoprotein fractions) between SHR and SHR-Lx under conditions of standard diet and standard diet + ATRA. We performed transcriptomic analysis of muscle tissue (m. soleus) in all groups using Affymetrix GeneChip Rat Gene 2.0 ST Arrays followed by Ingenuity Pathway Analysis and real-time PCR validation. RESULTS: In response to ATRA, SHR-Lx reacted with substantially greater rise in TG and C concentrations throughout the lipoprotein spectrum (two-way ANOVA strain * RA interaction significant for C content in chylomicrons (CM), VLDL and LDL as well as total, CM and HDL-TG). CONCLUSIONS: According to our modeling of metabolic and signalization pathways using differentially expressed genes we have identified a network with major nodes (including Sirt3, Il1b, Cpt1b and Pparg) likely to underlie the observed strain specific response to ATRA.

• MeSH
• Dyslipidemias blood   chemically induced   genetics   MeSH
• Muscle, Skeletal metabolism   MeSH
• Lipids blood   MeSH
• Lipid Metabolism MeSH
• Rats, Inbred SHR MeSH
• Transcriptome * MeSH
• Tretinoin MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Lipids MeSH
• Tretinoin 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
• Names of Substances
• CD36 Antigens MeSH
• Glucose MeSH

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics   MeSH
• DNA Primers MeSH
• DNA-Binding Proteins genetics   MeSH
• Genetic Linkage MeSH
• Genetic Markers MeSH
• Histone-Lysine N-Methyltransferase MeSH
• Rats genetics   MeSH
• Humans MeSH
• Chromosomes, Human, Pair 11 genetics   MeSH
• Chromosome Mapping * MeSH
• Molecular Sequence Data MeSH
• Polymorphism, Restriction Fragment Length MeSH
• Myeloid-Lymphoid Leukemia Protein MeSH
• Proto-Oncogenes * MeSH
• Deoxyribonucleases, Type II Site-Specific metabolism   MeSH
• Transcription Factors * MeSH
• Animals MeSH
• Check Tag
• Rats genetics   MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Names of Substances
• CYCGRG-specific type II deoxyribonucleases MeSH Browser
• DNA Primers MeSH
• DNA-Binding Proteins MeSH
• Genetic Markers MeSH
• Histone-Lysine N-Methyltransferase MeSH
• KMT2A protein, human MeSH Browser
• Mllt1 protein, rat MeSH Browser
• Myeloid-Lymphoid Leukemia Protein MeSH
• Deoxyribonucleases, Type II Site-Specific MeSH
• Transcription Factors * MeSH

• MeSH
• Chromosomes MeSH
• Genetic Linkage * MeSH
• Rats, Inbred Strains MeSH
• Rats MeSH
• Chromosome Mapping * MeSH
• Molecular Sequence Data MeSH
• Polymerase Chain Reaction MeSH
• Polymorphism, Restriction Fragment Length MeSH
• Receptors, Retinoic Acid genetics   MeSH
• Sequence Homology, Nucleic Acid MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Names of Substances
• Receptors, Retinoic Acid MeSH
• retinoic acid binding protein I, cellular MeSH Browser

The spontaneously hypertensive rat (SHR) is the most widely studied animal model of essential hypertension. Despite > 30 yr of research, the primary genetic lesions responsible for hypertension in the SHR remain undefined. In this report, we describe the construction and hemodynamic characterization of a congenic strain of SHR (SHR-Lx) that carries a defined segment of chromosome 8 from a normotensive strain of Brown-Norway rats (BN-Lx strain). Transfer of this segment of chromosome 8 from the BN-Lx strain onto the SHR background resulted in substantial reductions in systolic and diastolic blood pressure and cardiac mass. Linkage and comparative mapping studies indicate that the transferred chromosome segment contains a number of candidate genes for hypertension, including genes encoding a brain dopamine receptor and a renal epithelial potassium channel. These findings demonstrate that BP regulatory gene(s) exist within the differential chromosome segment trapped in the SHR-Lx congenic strain and that this region of chromosome 8 plays a major role in the hypertension of SHR vs. BN-Lx rats.

• MeSH
• Species Specificity MeSH
• Genotype MeSH
• Hypertension genetics   pathology   physiopathology   MeSH
• Blood Pressure genetics   MeSH
• Rats MeSH
• Chromosome Mapping * MeSH
• Molecular Sequence Data MeSH
• Rats, Inbred BN MeSH
• Rats, Inbred SHR MeSH
• Organ Size 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
• Research Support, U.S. Gov't, P.H.S. MeSH

We have constructed a genetic linkage map in the rat by analyzing the strain distribution patterns of 500 genetic markers in a large set of recombinant inbred strains derived from the spontaneously hypertensive rat and the Brown-Norway rat (HXB and BXH recombinant inbred strains). 454 of the markers could be assigned to specific chromosomes, and the amount of genome covered by the mapped markers was estimated to be 1151 centimorgans. By including a variety of morphologic, biochemical, immunogenetic, and molecular markers, the current map integrates and extends existing linkage data and should facilitate rat gene mapping and genetic studies of hypertension and other complex phenotypes of interest in the HXB and BXH recombinant inbred strains.

• MeSH
• DNA Primers MeSH
• Rats, Inbred Strains genetics   MeSH
• Crosses, Genetic MeSH
• Rats MeSH
• Chromosome Mapping * MeSH
• Molecular Sequence Data MeSH
• Mice MeSH
• Rats, Inbred BN MeSH
• Rats, Inbred SHR MeSH
• Recombination, Genetic MeSH
• Base Sequence MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA Primers MeSH

In the HXB and BXH recombinant inbred strains derived from the spontaneously hypertensive rat and the normotensive Brown Norway rat, we determined the strain distribution patterns of 500 genetic markers to scan the rodent genome for quantitative trait loci regulating cardiac mass and blood pressure. The markers spanned approximately 1,139 cM of the genome and were tested for correlations with left ventricular mass adjusted for body weight, and with systolic, diastolic, and mean arterial pressures. The marker for the dopamine 1A receptor (Drd1a) on chromosome 17 showed the strongest correlation with left ventricular heart weight (P = .00038, r = -0.59) and the relationship to heart weight was independent of blood pressure. The markers showing the strongest correlations with systolic, diastolic, and mean arterial pressure were D19Mit7 on chromosome 19 (P = .0012, r = .55), D2N35 on chromosome 2 (P = .0008, r = .56), and Il6 on chromosome 4 (P = .0018, r = .53), respectively. These studies demonstrate that the HXB and BXH strains can be effectively used for genome scanning studies of complex traits and have revealed several chromosome regions that may be involved in the genetic control of blood pressure and cardiac mass in the rat.

• MeSH
• Hypertension genetics   MeSH
• Blood Pressure * MeSH
• Rats MeSH
• Chromosome Mapping * MeSH
• Rats, Inbred BN MeSH
• Rats, Inbred SHR MeSH
• Recombination, Genetic MeSH
• Heart anatomy & histology   MeSH
• Organ Size MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH