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O Seda

Publications and source records attributed to O Seda.

14 recordsLinked to original sources
PubMed2006

Region of rat chromosome 8 determines complex nutrigenetic interactions under conditions of sucrose and cholesterol diets.

We have previously established a congenic strain SHR-Lx that carries a differential segment of rat chromosome 8 introgressed from a model of metabolic syndrome--the polydactylous rat strain--on the genomic background of spontaneously hypertensive rat (SHR). We compared the glucose tolerance and lipid profile of adult SHR and SHR-Lx males under conditions of standard diet and diets enriched in sucrose and cholesterol, respectively. While there was no evident difference between the SHR and SHR-Lx on standard diet, the one-week sucrose administration revealed the congenic strain sensitivity to carbohydrate-induced dyslipidemia conferred by the differential segment with only mild derangement of glucose tolerance. On the other hand, the high-cholesterol diet administration for three-weeks resulted in a contrasting pattern as the congenic strain displayed significantly lower concentrations of free fatty acids and improved glucose tolerance compared to SHR. After one-month washout period, the SHR-Lx showed higher insulin, triglyceride and cholesterol concentrations together with diminished insulin sensitivity of visceral adipose tissue. In summary, we have identified a genomic region syntenic to human chromosome 11q23, which determines complex nutrigenetic interactions under conditions of sucrose- and cholesterol-enriched diets.

Animal Nutritional Physiological Phenomena↗
PubMed2005

Quantitative founder-effect analysis of French Canadian families identifies specific loci contributing to metabolic phenotypes of hypertension.

The Saguenay-Lac St-Jean population of Quebec is relatively isolated and has genealogical records dating to the 17th-century French founders. In 120 extended families with at least one sib pair affected with early-onset hypertension and/or dyslipidemia, we analyzed the genetic determinants of hypertension and related cardiovascular and metabolic conditions. Variance-components linkage analysis revealed 46 loci after 100,000 permutations. The most prominent clusters of overlapping quantitative-trait loci were on chromosomes 1 and 3, a finding supported by principal-components and bivariate analyses. These genetic determinants were further tested by classifying families by use of LOD score density analysis for each measured phenotype at every 5 cM. Our study showed the founder effect over several generations and classes of living individuals. This quantitative genealogical approach supports the notion of the ancestral causality of traits uniquely present and inherited in distinct family classes. With the founder effect, traits determined within population subsets are measurably and quantitatively transmitted through generational lineage, with a precise component contributing to phenotypic variance. These methods should accelerate the uncovering of causal haplotypes in complex diseases such as hypertension and metabolic syndrome.

Adolescent↗
PubMed2005

A 14-gene region of rat chromosome 8 in SHR-derived polydactylous congenic substrain affects muscle-specific insulin resistance, dyslipidaemia and visceral adiposity.

The SHR and the PD/Cub are two established rodent models of human metabolic syndrome. Introgression of a ca 30 cM region of rat chromosome 8 from PD/Cub onto the genetic background of SHR was previously shown to influence several of the metabolic syndrome-related traits along with causing the PLS in the SHR-Lx congenic strain. In the process of identification of the causative alleles, we have produced several congenic sublines. The differential segment of SHR-Lx PD5 congenic substrain [SHR.PD(D8Rat42-D8Arb23)/Cub] spans approximately 1.4 Mb encompassing only 14 genes. When comparing the metabolic, morphometric and gene expression profiles of the SHR-Lx PD5 vs. SHR, the polydactyly and several distinct metabolic features observed in the original SHR-Lx congenic were still manifested, suggesting that the responsible genes were "trapped" within the relatively short differential segment of PD/Cub origin in SHR-Lx PD5. Particularly, the SHR-Lx PD5 displayed substantial reduction of insulin sensitivity confined to skeletal muscle. Among the candidate genes, the promyelocytic leukaemia zinc-finger Plzf (Zbtb16) transcription repressor is most likely responsible for the Lx mutation resulting in PLS and could also be involved in the alteration of metabolic pathways. The sequence analysis of the Plzf gene revealed a SNP leading to a threonine to serine substitution in SHR at aminoacid position 208 (T208S). In summary, we have isolated a 1.4 Mb genomic region syntenic to human chromosome 11q23, which, apart from causing polydactyly-luxate syndrome (PLS), affects total body weight, adiposity, lipid profile, insulin sensitivity of skeletal muscle and related gene expression as shown in the SHR-Lx PD5 congenic substrain.

Adipose Tissue↗
PubMed2004

Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome.

OBJECTIVE: To investigate the effect of transcription-modulating drugs, fenofibrate and isotretinoin, on metabolic profile, insulin sensitivity of adipose and muscle tissues and gene expression in a genetic model of insulin resistance syndrome, polydactylous rat strain (PD/Cub). DESIGN: Administration of fenofibrate (100 mg/kg/day), isotretinoin (30 mg/kg/day) or vehicle to adult male PD/Cub rats fed standard laboratory chow for 15 days. MEASUREMENTS: Parameters of lipid and carbohydrate metabolism-oral glucose tolerance test, serum concentrations of insulin, triglycerides (TG), free fatty acids (FFA), glycerol, total cholesterol (CH); morphometric variables, in vitro insulin sensitivity of adipose and muscle tissues, catecholamine-stimulated lipolysis and the expression of ApoC-III and Hnf-4 genes in liver. RESULTS: Both experimental groups displayed an increase in adiposity with contrasting effects on TG (lowered by fenofibrate and increased by isotretinoin) and gene expression (no change in fibrate-treated rats and increased expression of ApoC-III and Hnf-4 in isotretinoin-treated group). Fenofibrate-treated rats also showed decreased concentrations of FFA and CH with concomitant decrease of catecholamine-induced lipolysis in adipocytes, but also hyperinsulinemia and the highest insulin/glucose ratio. Isotretinoin increased glycerol concentrations and decreased the insulin sensitivity of peripheral tissues. CONCLUSION: The PD/Cub rat showed a distinct pharmacogenetic reaction to fenofibrate and isotretinoin administration. Several lines of evidence now implicate specific variant(s) of ApoC-III and/or ApoA-V alleles as responsible for the dyslipidemia observed in this genetic model. The PD/Cub strain may also serve as a pharmacogenetic model for dissection of the retinoid-induced hypertriglyceridemia.

Adipose Tissue↗
PubMed2004

Comparative gene map of hypertriglyceridaemia.

Elevated triglyceride levels in the circulation are currently recognized as an independent risk factor for coronary artery disease. Hypertriglyceridaemia represents one of the attributes of metabolic syndrome and is present in the most common genetic dyslipidaemia, the familial combined hyperlipidaemia. The factual concentration of triglycerides is determined by a complex interaction of environmental and genetic components. Deeper understanding of the causative gene variants and the mode of their participation in the pathogenesis of hypertriglyceridaemia is required for devising efficient therapy of hypertriglyceridaemia. This is the first systematic review of linkage and candidate gene studies dealing with the dissection of genetic determinants of (hyper)triglyceridaemia in human and two major mammalian model species, mouse and rat. Based on the merged sets of data, a synthetic view of the genetic component of triglyceridaemia, the "hypertriglyceridaemia gene map", is presented.

Animals↗
PubMed2004

[Nutrition genomics].

The importance of nutrition for human health and its influence on the onset and course of many diseases are nowadays considered as proven. Only the recent development of molecular biology and biochemical methods allows the elucidation of the molecular mechanisms of diet constituent actions and their subsequent effect on homeostatic mechanisms in health and disease states. The availability of the draft human genome sequence as well as the genome sequences of model organisms, combined with the functional and integrative genomics approaches of systems biology, bring about the possibility to identify alleles and haplotypes responsible for specific reaction to the dietary challenge in susceptible individuals. Such complex interactions are studied within the newly conceived field, the nutrition genomics (nutrigenomics). Using the tools of highly parallel analyses of transcriptome, proteome and metabolome, the nutrition genomics pursues its ultimate goal, i.e. the individualized diet, respecting not only quantitative and qualitative nutritional needs and the actual health status, but also the genetic predispositions of an individual. This approach should lead to prevention of the onset of such diseases as obesity, hypertension or type 2 diabetes, or enhance the efficiency of their therapy.

Animals↗
PubMed2004

PPARs: molecular targets in the pharmacogenomics era.

The recent global increase in prevalence of diseases like obesity, type 2 diabetes and hypertension in westernized societies is unfortunately not paralleled by our full understanding of the causative mechanisms. It is now firmly established that the interacting genetic and environmental (diet, smoking) components together determine the development and severity of the particular condition, which makes detailed dissection of such complex traits even more complicated. In effect, there is an unmet urgent need for molecular targets so we can directly modulate the causative factors and devise effective preventive and therapeutic algorithms. Among the most promising molecular targets for treatment of metabolic syndrome-related conditions identified so far, the group of three lipid-sensors, the peroxisome proliferator-activated receptors (PPARs) clearly stands out. The review focuses on pharmacogenetic aspects of recent developments in PPAR biology.

Animals↗
PubMed2003

Differential linkage of triglyceride and glucose levels on rat chromosome 4 in two segregating rat populations.

The PD/Cub is a recently established model of the IRS. The BN.SHR4 congenic strain was derived by introgression of the chromosome 4 segment of SHR origin (including the defective Cd36/Fat allele) onto the BN/Cub genetic background. We investigated the linkage of metabolic and morphometric phenotypes (total body weight, OGTT, fasting serum levels of TG, FFA) on chromosome 4 in two separate F2 rat populations: the PD/Cub x BN/Cub and PD/Cub x BN.SHR4 (total N = 243). In the PD/Cub x BN.SHR4 F2s, we found significant linkage for fasting TG levels (LOD = 3.26) and suggestive linkage for fasting glycaemia (LOD = 2.80) in the interval Il-6 - D4Bro1, i.e. the part of chromosome 4 of SHR origin in the BN.SHR4 congenic. However, no linkage for fasting TG concentrations, fasting glycaemia or any other followed parameter was found in the second, PD/Cub x BN/Cub F2. The differential linkage of TG and glucose levels to the centromeric part of rat chromosome 4q in the studied F2s points to the importance of this region for the lipid and carbohydrate metabolism at the specific age (10 months) and diet (standard chow) combination. The Cd36/Fat and Il-6 genes are the preliminary positional candidates for the observed effect.

Animals↗
PubMed2003

New apolipoprotein A-V: comparative genomics meets metabolism.

The availability of the human genome sequence and the recently completed draft sequences of two major mammalian model species, the mouse (Mus musculus) and the rat (Rattus norvegicus), allow researchers to apply novel approaches for gene identification and characterization, using methods of comparative and functional genomics. Recently, a new gene coding for apolipoprotein A-V was identified in the vicinity of APOA-I/C-III/A-IV cluster on human chromosome 11q23 by comparative sequencing method. In a relatively short time, compelling evidence accumulated for the substantial role of APOA-V in lipid metabolism. Studies in knock-out and transgenic mice revealed that its expression pattern correlates negatively with triglyceride levels. This observation was verified in human population studies in variety of ethnic and age groups. Several single nucleotide polymorphisms were described and particular SNP alleles and haplotypes in the APO A-V gene region were shown to be associated with dyslipidemia. The discovery and characterization of the APO A-V demonstrates current possibilities of the integrative approaches in biology, boosted by the available bioinformatic tools.

Amino Acid Sequence↗
PubMed2002

Metabolic characterization of insulin resistance syndrome feature loci in three brown Norway-derived congenic strains.

Studies on genetic determination of the insulin resistance syndrome in rat models revealed several susceptibility loci for features of this complex phenotype, i.e. dyslipidemia, insulin resistance and obesity. We analysed the influence of introgression of the RNO4, RNO20 segments of SHR origin and RNO8 segment of PD/Cub origin (all previously shown to be involved in (dys)regulation of carbohydrate and lipid metabolism) onto the genetic background of a common progenitor, the Brown Norway (BN/Cub) rat. The differential segments were genetically characterized in the BN.PD-D8Rat39/D8Rat35 (BN-Lx, RNO8 congenic), BN.SHR-Il6/Cd36 (BN.SHR4, RNO4 congenic) and BN.PD-D8Rat39/D8Rat3, SHR-D4Mgh2/Cd36,SHR-D20Wox3/D20Mgh5 (BN-Lx 1K, RNO4, 8, 20 triple congenic) strains and their metabolic profiling was performed. After one week of high-sucrose diet, all congenic strains showed substantially higher levels of serum triglycerides and free fatty acids as well as impaired glucose tolerance in comparison with the BN/Cub progenitor strain. The BN-Lx 1K triple congenic strain displayed the most profound dyslipidemia, glucose intolerance and highest increase of triglyceridemia in response to high-sucrose diet overall, though accompanied with the significantly lowest adiposity index. These results further support the role of genes present within the studied chromosomal regions in observed metabolic disturbances. Furthermore, these findings point to the studied loci within the gene-gene and gene-environment interactions involved in pathogenesis of the insulin resistance syndrome. The set of defined congenic strains provides a possibility of assessing individual features of such a complex phenotype.

Animals↗
PubMed2002

Rosiglitazone improves insulin resistance, lipid profile and promotes adiposity in a genetic model of metabolic syndrome X.

RSG is a member of the TZD group of drugs widely used in treatment of type 2 diabetes. The underlying mechanism of TZD action in insulin-sensitive tissues is not fully understood. In this study we show that 14-day RSG administration in a new rodent model of metabolic syndrome X, polydactylous rat strain (PD/Cub), substantially improves its lipid profile (serum TGs 4.20 +/- 0.23 vs 2.34 +/- 0.14 mmol/l, P < 0.0001; FFA 0.46 +/- 0.05 vs 0.33 +/- 0.02 mmol/l, P = 0.017), diminishes the liver TG depots (15.76 +/- 0.60 vs 8.44 +/- 0.55 micromol/g, P < 0.0001), serum insulin concentrations (1.10 +/- 0.08 vs 0.63 +/- 0.02 nmol/l, P < 0.0001) and promotes visceral adiposity (adiposity index 1.28 +/- 0.03 vs 1.85 +/- 0.07, P < 0.0001). No changes were observed in serum or liver concentrations of cholesterol. Concomitantly, both basal and insulin-stimulated glycogen synthesis in red-fibre type muscle (m. soleus) was enhanced, as well as glucose uptake into adipose tissue. However, glucose oxidation in soleus (basal and insulin-stimulated) remained unchanged. In consent with previously published data we suggest the current pharmacogenetic study as a further proof of substantial influence of genetic background on the physiological outcome of TZD therapy.

Adipose Tissue↗
PubMed2000

Rat inbred PD/cub strain as a model of dyslipidemia and insulin resistance.

Genome scan and metabolic profile of the PD/Cub rat inbred strain in comparison with SHR and BN strains is presented. The PD/Cub strain has been bred by brother sister mating for more than 60 generations since 1969. Its highly inbred status has been confirmed by PCR genotyping with more than 170 microsatellite markers. No case of residual heterozygosity has been recorded. Accordingly, the values obtained by the analysis of metabolic phenotypes are homogeneous with low variance. The PD/Cub strain has significantly higher triglyceride levels and epididymal fat weight as compared to both SHR and BN strains. The PD strain also displays the lowest incorporation of 14C-U glucose into the epididymal adipose tissue. The data on glucose metabolism clearly indicate that the PD/Cub strain is insulin resistant. Genetic homogeneity and reproducibility of experimental results qualify the PD/Cub rats as an animal model for analysis of the syndrome X.

Adipose Tissue↗