Metabolic syndrome (MetS) is a cluster of risk factors that increase the likelihood of developing cardiovascular, metabolic and other diseases. The pharmacological management of MetS often involves polypharmacy, making it essential to understand how drug-metabolising enzymes, transporters, transcription factors and other proteins involved are affected under different metabolic conditions. This study investigated the relative mRNA expression of key hepatic and intestinal genes involved in drug metabolism, including Cyp1a2, Cyp3a23, Cyp2d1, Cyp2c11, Cyp2c6, Cyp2e1, Cyp7a1, Cyp2b1, Cyp2a1, Abcg5, Abcg8, Abcb1, Nr1i3, Nr1i2, Ahr, Gsta1 and Comt, in four nonobese rat models of MetS: hereditary hypertriglyceridaemic (HHTg), spontaneously hypertensive rat (SHR), SHR expressing transgenic human C-reactive protein (SHR-CRP), and bilaterally ovariectomised Wistar (W-OVX), compared to Wistar controls. Gene expression was quantified by RT-PCR with data normalised using the ΔΔCt method. Between the models studied, measurements showed significant differences in the liver. The upregulation of Cyp2c6 and Cyp3a23 was observed only in SHR; upregulated Cyp2d1 was found in SHR as well as in HHTg rats. The downregulated Cyp1a2 was measured in a condition of hypertriglyceridemia, postmenopause or hypertension. These findings highlight model-specific alterations in gene expression that may affect drug metabolism and interactions. The HHTg may be, in particular, a suitable model for preclinical studies focusing on intestinal drug-drug interactions in MetS-related conditions.

• Keywords
• drug metabolism, metabolic syndrome, rat model,
• MeSH
• Liver metabolism   enzymology   MeSH
• Rats MeSH
• Humans MeSH
• Membrane Transport Proteins * genetics   metabolism   MeSH
• RNA, Messenger * metabolism   genetics   MeSH
• Metabolic Syndrome * genetics   metabolism   MeSH
• Disease Models, Animal MeSH
• Rats, Inbred SHR MeSH
• Rats, Wistar MeSH
• Receptors, Cytoplasmic and Nuclear * genetics   metabolism   MeSH
• Cytochrome P-450 Enzyme System * genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Membrane Transport Proteins * MeSH
• RNA, Messenger * MeSH
• Receptors, Cytoplasmic and Nuclear * MeSH
• Cytochrome P-450 Enzyme System * MeSH

Thermogenesis in brown adipose tissue (BAT) uses intracellular triglycerides, circulating free fatty acids and glucose as the main substrates. The objective of the current study was to analyse the role of CD36 fatty acid translocase in regulation of glucose and fatty acid utilisation in BAT. BAT isolated from spontaneously hypertensive rat (SHR) with mutant Cd36 gene and SHR-Cd36 transgenic rats with wild type variant was incubated in media containing labeled glucose and palmitate to measure substrate incorporation and oxidation. SHR-Cd36 versus SHR rats showed significantly increased glucose incorporation into intracellular lipids associated with reduced glycogen synthase kinase 3β (GSK-3β) protein expression and phosphorylation and increased oxidation of exogenous palmitate. It can be concluded that CD36 enhances glucose transport for lipogenesis in BAT by suppressing GSK-3β and promotes direct palmitate oxidation.

• MeSH
• CD36 Antigens * genetics   metabolism   MeSH
• Glucose metabolism   MeSH
• Adipose Tissue, Brown * metabolism   MeSH
• Glycogen Synthase Kinase 3 beta metabolism   MeSH
• Rats MeSH
• Fatty Acids metabolism   MeSH
• Palmitates metabolism   MeSH
• Rats, Inbred SHR MeSH
• Rats, Transgenic MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CD36 Antigens * MeSH
• Glucose MeSH
• Glycogen Synthase Kinase 3 beta MeSH
• Fatty Acids MeSH
• Palmitates MeSH

Several corresponding regions of human and mammalian genomes have been shown to affect sensitivity to the manifestation of metabolic syndrome via nutrigenetic interactions. In this study, we assessed the effect of sucrose administration in a newly established congenic strain BN.SHR20, in which a limited segment of rat chromosome 20 from a metabolic syndrome model, spontaneously hypertensive rat (SHR), was introgressed into Brown Norway (BN) genomic background. We mapped the extent of the differential segment and compared the genomic sequences of BN vs. SHR within the segment in silico. The differential segment of SHR origin in BN.SHR20 spans about 9 Mb of the telomeric portion of the short arm of chromosome 20. We identified non-synonymous mutations e.g., in ApoM, Notch4, Slc39a7, Smim29 genes and other variations in or near genes associated with metabolic syndrome in human genome-wide association studies. Male rats of BN and BN.SHR20 strains were fed a standard diet for 18 weeks (control groups) or 16 weeks of standard diet followed by 14 days of high-sucrose diet (HSD). We assessed the morphometric and metabolic profiles of all groups. Adiposity significantly increased only in BN.SHR20 after HSD. Fasting glycemia and the glucose levels during the oral glucose tolerance test were higher in BN.SHR20 than in BN groups, while insulin levels were comparable. The fasting levels of triacylglycerols were the highest in sucrose-fed BN.SHR20, both compared to the sucrose-fed BN and the control BN.SHR20. The non-esterified fatty acids and total cholesterol concentrations were higher in BN.SHR20 compared to their respective BN groups, and the HSD elicited an increase in non-esterified fatty acids only in BN.SHR20. In a new genetically defined model, we have isolated a limited genomic region involved in nutrigenetic sensitization to sucrose-induced metabolic disturbances.

• Keywords
• animal model, congenic rat, metabolic syndrome, nutrigenetics,
• MeSH
• Apolipoproteins M genetics   MeSH
• Genome-Wide Association Study MeSH
• Hypertension * metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Chromosomes, Human, Pair 20 metabolism   MeSH
• Fatty Acids MeSH
• Metabolic Syndrome * genetics   metabolism   MeSH
• Nutrigenomics MeSH
• Fasting MeSH
• Rats, Inbred BN MeSH
• Rats, Inbred SHR MeSH
• Cation Transport Proteins * genetics   MeSH
• Sucrose adverse effects   MeSH
• Mammals genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Apolipoproteins M MeSH
• Apom protein, rat MeSH Browser
• Fatty Acids MeSH
• Cation Transport Proteins * MeSH
• Sucrose MeSH
• SLC39A7 protein, human MeSH Browser

Mutations of the TMEM70 gene disrupt the biogenesis of the ATP synthase and represent the most frequent cause of autosomal recessive encephalo-cardio-myopathy with neonatal onset. Patient tissues show isolated defects in the ATP synthase, leading to the impaired mitochondrial synthesis of ATP and insufficient energy provision. In the current study, we tested the efficiency of gene complementation by using a transgenic rescue approach in spontaneously hypertensive rats with the targeted Tmem70 gene (SHR-Tmem70ko/ko), which leads to embryonic lethality. We generated SHR-Tmem70ko/ko knockout rats expressing the Tmem70 wild-type transgene (SHR-Tmem70ko/ko,tg/tg) under the control of the EF-1α universal promoter. Transgenic rescue resulted in viable animals that showed the variable expression of the Tmem70 transgene across the range of tissues and only minor differences in terms of the growth parameters. The TMEM70 protein was restored to 16-49% of the controls in the liver and heart, which was sufficient for the full biochemical complementation of ATP synthase biogenesis as well as for mitochondrial energetic function in the liver. In the heart, we observed partial biochemical complementation, especially in SHR-Tmem70ko/ko,tg/0 hemizygotes. As a result, this led to a minor impairment in left ventricle function. Overall, the transgenic rescue of Tmem70 in SHR-Tmem70ko/ko knockout rats resulted in the efficient complementation of ATP synthase deficiency and thus in the successful genetic treatment of an otherwise fatal mitochondrial disorder.

• Keywords
• ATP synthase deficiency, TMEM70 factor, gene therapy, mitochondria disease, transgenic rescue,
• Publication type
• Journal Article MeSH

Methylglyoxal (MG), a potent precursor of advanced glycation end-products (AGE), is increased in metabolic disorders such as diabetes and obesity. MG and other dicarbonyl metabolites are detoxified by the glyoxalase system in which glyoxalase 1, coded by the Glo1 gene, serves as the rate-limiting enzyme. In this study, we analyzed the effects of Glo1 downregulation on glucose and lipid metabolism parameters in spontaneously hypertensive rats (SHR) by targeting the Glo1 gene (SHR-Glo1+/- heterozygotes). Compared to SHR wild-type animals, SHR-Glo1+/- rats showed significantly reduced Glo1 expression and lower GLO1 activity in tissues associated with increased MG levels. In contrast to SHR controls, SHR-Glo1+/- rats exhibited lower relative weight of epididymal fat, reduced ectopic fat accumulation in the liver and heart, and decreased serum triglycerides. In addition, compared to controls, SHR-Glo1+/- rats showed reduced serum insulin and increased basal and insulin stimulated incorporation of glucose into white adipose tissue lipids (lipogenesis). Reduced ectopic fat accumulation in the heart was associated with significantly increased pAMPK/AMPK ratio and GLUT4 activity. These results provide evidence that Glo1 downregulation in SHR is associated with reduced adiposity and ectopic fat accumulation, most likely mediated by AMPK activation in the heart.

• Keywords
• AMPK, GLUT4, Glo1 gene knockdown, adipose tissue, heart, insulin resistance, methylglyoxal, spontaneously hypertensive rat,
• Publication type
• Journal Article MeSH

Brown adipose tissue (BAT) has been suggested to play an important role in lipid and glucose metabolism in rodents and possibly also in humans. In the current study, we used genetic and correlation analyses in the BXH/HXB recombinant inbred (RI) strains, derived from Brown Norway (BN) and spontaneously hypertensive rats (SHR), to identify genetic determinants of BAT function. Linkage analyses revealed a quantitative trait locus (QTL) associated with interscapular BAT mass on chromosome 4 and two closely linked QTLs associated with glucose oxidation and glucose incorporation into BAT lipids on chromosome 2. Using weighted gene coexpression network analysis (WGCNA) we identified 1,147 gene coexpression modules in the BAT from BXH/HXB rats and mapped their module eigengene QTLs. Through an unsupervised analysis, we identified modules related to BAT relative mass and function. The Coral4.1 coexpression module is associated with BAT relative mass (includes Cd36 highly connected gene), and the Darkseagreen coexpression module is associated with glucose incorporation into BAT lipids (includes Hiat1, Fmo5, and Sort1 highly connected transcripts). Because multiple statistical criteria were used to identify candidate modules, significance thresholds for individual tests were not adjusted for multiple comparisons across modules. In summary, a systems genetic analysis using genomic and quantitative transcriptomic and physiological information has produced confirmation of several known genetic factors and significant insight into novel genetic components functioning in BAT and possibly contributing to traits characteristic of the metabolic syndrome.

• Keywords
• brown adipose tissue, coexpression modules, quantitative trait locus, recombinant inbred strains, spontaneously hypertensive rat,
• MeSH
• Genetic Predisposition to Disease genetics   MeSH
• Glucose metabolism   MeSH
• Adipose Tissue, Brown metabolism   MeSH
• Rats MeSH
• Quantitative Trait Loci genetics   MeSH
• Metabolic Syndrome genetics   metabolism   MeSH
• Rats, Inbred BN MeSH
• Rats, Inbred SHR 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, N.I.H., Extramural MeSH
• Names of Substances
• Glucose MeSH

We previously mapped hypertension-related insulin resistance quantitative trait loci (QTLs) to rat chromosomes 4, 12 and 16 using adipocytes from F2 crosses between spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats, and subsequently identified Cd36 as the gene underlying the chromosome 4 locus. The identity of the chromosome 12 and 16 genes remains unknown. To identify whole-body phenotypes associated with the chromosome 12 and 16 linkage regions, we generated and characterised new congenic strains, with WKY donor segments introgressed onto an SHR genetic background, for the chromosome 12 and 16 linkage regions. We found a >50% increase in insulin sensitivity in both the chromosome 12 and 16 strains. Blood pressure and left ventricular mass were reduced in the two congenic strains consistent with the congenic segments harbouring SHR genes for insulin resistance, hypertension and cardiac hypertrophy. Integrated genomic analysis, using physiological and whole-genome sequence data across 42 rat strains, identified variants within the congenic regions in Upk3bl, RGD1565131 and AABR06087018.1 that were associated with blood pressure, cardiac mass and insulin sensitivity. Quantitative trait transcript analysis across 29 recombinant inbred strains showed correlation between expression of Hspb1, Zkscan5 and Pdgfrl with adipocyte volume, systolic blood pressure and cardiac mass, respectively. Comparative genome analysis showed a marked enrichment of orthologues for human GWAS-associated genes for insulin resistance within the syntenic regions of both the chromosome 12 and 16 congenic intervals. Our study defines whole-body phenotypes associated with the SHR chromosome 12 and 16 insulin-resistance QTLs, identifies candidate genes for these SHR QTLs and finds human orthologues of rat genes in these regions that associate with related human traits. Further study of these genes in the congenic strains will lead to robust identification of the underlying genes and cellular mechanisms.

• Keywords
• Congenic, Genomic, Hypertension, Insulin resistance, Rat,
• MeSH
• Genome-Wide Association Study MeSH
• Energy Metabolism genetics   MeSH
• Genomics * MeSH
• Homeostasis MeSH
• Hypertension genetics   physiopathology   MeSH
• Insulin pharmacology   MeSH
• Insulin Resistance genetics   MeSH
• Liver drug effects   metabolism   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Calorimetry MeSH
• Cardiomegaly genetics   physiopathology   MeSH
• Muscle, Skeletal drug effects   metabolism   MeSH
• Blood Pressure drug effects   MeSH
• Humans MeSH
• Quantitative Trait Loci genetics   MeSH
• Rats, Inbred SHR MeSH
• Gene Expression Regulation drug effects   MeSH
• Chromosomes, Mammalian genetics   MeSH
• Heart Ventricles drug effects   pathology   MeSH
• Feeding Behavior drug effects   MeSH
• Body Weight drug effects   MeSH
• Triglycerides metabolism   MeSH
• Organ Size drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Insulin MeSH
• Triglycerides MeSH

Disruption to the sensitive balance of long-chain fatty acids and glucose in the heart could cause cardiovascular diseases. Searching for a possible role of novel protein kinase C (nPKC) in heart with disrupted energy balance, we compared the insulin-resistant spontaneously hypertensive rats (SHR), which carry a nonfunctional variant of the fatty acid transporter FAT/CD36, with the less insulin-resistant congenic strain SHR-4 that is genetically identical except for a segment on chromosome 4 including a wild-type gene for a functional FAT/CD36. We analyzed expression of the nPKC-δ and -ε isoforms plus triacylglycerols (TAG) content in the myocardium of both FAT/CD36 strains and after a high sucrose diet (HSD). Two weeks before killing, males of both strains were randomly divided into two groups and fed either a standard laboratory chow or an HSD. PKC was determined by Western blotting in particulate and cytosolic fractions from left ventricles. The SHR-4 rats exhibited lower serum levels of insulin and free fatty acids than did SHR rats and higher amounts of PKC-ε in the heart particulate fraction. HSD caused accumulation of heart TAG in SHR but not in SHR-4. HSD increased PKC-δ and decreased PKC-ε expression in particulate fraction from left ventricles of SHR-4 while having no effects in SHR. These results demonstrate that reduced insulin resistance in SHR-4 rats with wild-type FAT/CD36 is associated with the insulin signaling pathway involving nPKCs.

• MeSH
• Enzyme Activation MeSH
• CD36 Antigens genetics   metabolism   MeSH
• Cytosol metabolism   MeSH
• Insulin blood   metabolism   MeSH
• Insulin Resistance genetics   physiology   MeSH
• Blood Glucose analysis   metabolism   MeSH
• Rats MeSH
• Fatty Acids, Nonesterified blood   metabolism   MeSH
• Myocardium metabolism   MeSH
• Rats, Inbred SHR MeSH
• Protein Kinase C-delta biosynthesis   MeSH
• Protein Kinase C-epsilon biosynthesis   MeSH
• Gene Expression Regulation MeSH
• Sucrose metabolism   MeSH
• Signal Transduction MeSH
• Heart Ventricles metabolism   MeSH
• Triglycerides blood   metabolism   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
• Insulin MeSH
• Blood Glucose MeSH
• Fatty Acids, Nonesterified MeSH
• Protein Kinase C-delta MeSH
• Protein Kinase C-epsilon MeSH
• Sucrose MeSH
• Triglycerides 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
• Names of Substances
• DNA, Mitochondrial MeSH
• Transposases MeSH

Hypertension in humans and experimental models has a strong hereditary basis, but identification of causative genes remains challenging. Quantitative trait loci (QTLs) for hypertension and salt sensitivity have been reported on rat chromosome 18. We set out to genetically isolate and prioritize genes within the salt-sensitivity and hypertension QTLs on the spontaneously hypertensive rat (SHR) chromosome 18 by developing and characterizing a series of congenic strains derived from the SHR and normotensive Brown Norway rat strains. The SHR.BN-D18Rat113/D18Rat82 congenic strain exhibits significantly lower blood pressure and is salt resistant compared with the SHR. Transplantation of kidneys from SHR.BN-D18Rat113/D18Rat82 donors into SHR recipients is sufficient to attenuate increased blood pressure but not salt sensitivity. Derivation of congenic sublines allowed for the separation of salt sensitivity from hypertension QTL regions. Renal expression studies with microarray and Solexa-based sequencing in parental and congenic strains identified 4 differentially expressed genes within the hypertension QTL region, one of which is an unannotated transcript encoding a previously undescribed, small, nonprotein coding RNA. Sequencing selected biological candidate genes within the minimal congenic interval revealed a nonsynonymous variant in SHR transcription factor 4. The minimal congenic interval is syntenic to a region of human chromosome 18 where significant linkage to hypertension was observed in family based linkage studies. These congenic lines provide reagents for identifying causative genes that underlie the chromosome 18 SHR QTLs for hypertension and salt sensitivity. Candidate genes identified in these studies merit further investigation as potentially causative hypertension genes in SHR and human hypertension.

• MeSH
• Genetic Predisposition to Disease genetics   MeSH
• Hypertension etiology   genetics   physiopathology   MeSH
• Polymorphism, Single Nucleotide MeSH
• Blood Pressure genetics   physiology   MeSH
• Rats MeSH
• Sodium Chloride, Dietary adverse effects   MeSH
• Kidney metabolism   MeSH
• Quantitative Trait Loci genetics   MeSH
• Chromosome Mapping MeSH
• Blotting, Northern MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Rats, Inbred BN MeSH
• Rats, Inbred SHR MeSH
• Apoptosis Regulatory Proteins genetics   MeSH
• Receptor, Melanocortin, Type 2 genetics   MeSH
• Receptor, Melanocortin, Type 4 genetics   MeSH
• Receptors, Melanocortin genetics   MeSH
• Chromosomes, Mammalian genetics   MeSH
• Oligonucleotide Array Sequence Analysis MeSH
• Gene Expression Profiling MeSH
• Kidney Transplantation methods   MeSH
• Protein Tyrosine Phosphatase, Non-Receptor Type 2 genetics   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, N.I.H., Extramural MeSH
• Names of Substances
• CIDEA protein, rat MeSH Browser
• Sodium Chloride, Dietary MeSH
• melanocortin 5 receptor MeSH Browser
• Apoptosis Regulatory Proteins MeSH
• Ptpn2 protein, rat MeSH Browser
• Receptor, Melanocortin, Type 2 MeSH
• Receptor, Melanocortin, Type 4 MeSH
• Receptors, Melanocortin MeSH
• Protein Tyrosine Phosphatase, Non-Receptor Type 2 MeSH