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Pathophysiological, genetic and gene expression features of a novel rodent model of the cardio-metabolic syndrome.

Wallis RH, Collins SC, Kaisaki PJ, Argoud K, Wilder SP, Wallace KJ, Ria M, Ktorza A, Rorsman P, Bihoreau MT, Gauguier D - PLoS ONE (2008)

Bottom Line: Complex etiology and pathogenesis of pathophysiological components of the cardio-metabolic syndrome have been demonstrated in humans and animal models.Genotype analysis of single nucleotide polymorphisms (SNPs) in strains genetically related to the GK highlights clusters of conserved and strain-specific variants in RNO1 that can assist the identification of naturally occurring variants isolated in diabetic and hypertensive strains when different phenotype selection procedures were applied.Our results emphasize the importance of rat congenic models for defining the impact of genetic variants in well-characterised QTL regions on in vivo pathophysiological features and cis-/trans- regulation of gene expression.

View Article: PubMed Central - PubMed

Affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

ABSTRACT

Background: Complex etiology and pathogenesis of pathophysiological components of the cardio-metabolic syndrome have been demonstrated in humans and animal models.

Methodology/principal findings: We have generated extensive physiological, genetic and genome-wide gene expression profiles in a congenic strain of the spontaneously diabetic Goto-Kakizaki (GK) rat containing a large region (110 cM, 170 Mb) of rat chromosome 1 (RNO1), which covers diabetes and obesity quantitative trait loci (QTL), introgressed onto the genetic background of the normoglycaemic Brown Norway (BN) strain. This novel disease model, which by the length of the congenic region closely mirrors the situation of a chromosome substitution strain, exhibits a wide range of abnormalities directly relevant to components of the cardio-metabolic syndrome and diabetes complications, including hyperglycaemia, hyperinsulinaemia, enhanced insulin secretion both in vivo and in vitro, insulin resistance, hypertriglyceridemia and altered pancreatic and renal histological structures. Gene transcription data in kidney, liver, skeletal muscle and white adipose tissue indicate that a disproportionately high number (43-83%) of genes differentially expressed between congenic and BN rats map to the GK genomic interval targeted in the congenic strain, which represents less than 5% of the total length of the rat genome. Genotype analysis of single nucleotide polymorphisms (SNPs) in strains genetically related to the GK highlights clusters of conserved and strain-specific variants in RNO1 that can assist the identification of naturally occurring variants isolated in diabetic and hypertensive strains when different phenotype selection procedures were applied.

Conclusions: Our results emphasize the importance of rat congenic models for defining the impact of genetic variants in well-characterised QTL regions on in vivo pathophysiological features and cis-/trans- regulation of gene expression. The congenic strain reported here provides a novel and sustainable model for investigating the pathogenesis and genetic basis of risks factors for the cardio-metabolic syndrome.

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Related in: MedlinePlus

Follow-up measure of body weight in BN, GK and BN.GK-Nidd/gk1 congenic rats (A), and retroperitoneal fat pad (RFP) weight (B) and adiposity index (C) in 24 weeks old rats.Data are expressed as means±SEM. Number of rats tested is in parentheses. *P<0.01 significantly different between congenic and BN rats. †P<0.01 significantly different between congenic and GK rats.
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pone-0002962-g001: Follow-up measure of body weight in BN, GK and BN.GK-Nidd/gk1 congenic rats (A), and retroperitoneal fat pad (RFP) weight (B) and adiposity index (C) in 24 weeks old rats.Data are expressed as means±SEM. Number of rats tested is in parentheses. *P<0.01 significantly different between congenic and BN rats. †P<0.01 significantly different between congenic and GK rats.

Mentions: Body weight at 2 weeks was higher in congenics than in BN (Fig. 1A) (P = 4.9×10−7). At weaning (4 weeks) body weight was not statistically different between the two groups, but at 12 and 24 weeks, congenic rats were significantly heavier than BN controls (P = 3.2×10−7 and 3.8×10−6, respectively). Congenic rats were heavier than GK until weaning. At 12 and 24 weeks, GK rats were significantly heavier than congenics. RFP weight was significantly higher in congenics than in BN rats (Fig. 1B). As a consequence adiposity index was increased in congenics when compared to BN (Fig. 1C), but this effect was statistically significant (P = 3.3×10−4) in females only (data not shown). Both RFP weight and adiposity index were significantly lower in congenics than in GK rats. Overall these data indicate that GK genetic variants in the congenics account for a proportion of the phenotypic differences between GK and BN rats.


Pathophysiological, genetic and gene expression features of a novel rodent model of the cardio-metabolic syndrome.

Wallis RH, Collins SC, Kaisaki PJ, Argoud K, Wilder SP, Wallace KJ, Ria M, Ktorza A, Rorsman P, Bihoreau MT, Gauguier D - PLoS ONE (2008)

Follow-up measure of body weight in BN, GK and BN.GK-Nidd/gk1 congenic rats (A), and retroperitoneal fat pad (RFP) weight (B) and adiposity index (C) in 24 weeks old rats.Data are expressed as means±SEM. Number of rats tested is in parentheses. *P<0.01 significantly different between congenic and BN rats. †P<0.01 significantly different between congenic and GK rats.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2500170&req=5

pone-0002962-g001: Follow-up measure of body weight in BN, GK and BN.GK-Nidd/gk1 congenic rats (A), and retroperitoneal fat pad (RFP) weight (B) and adiposity index (C) in 24 weeks old rats.Data are expressed as means±SEM. Number of rats tested is in parentheses. *P<0.01 significantly different between congenic and BN rats. †P<0.01 significantly different between congenic and GK rats.
Mentions: Body weight at 2 weeks was higher in congenics than in BN (Fig. 1A) (P = 4.9×10−7). At weaning (4 weeks) body weight was not statistically different between the two groups, but at 12 and 24 weeks, congenic rats were significantly heavier than BN controls (P = 3.2×10−7 and 3.8×10−6, respectively). Congenic rats were heavier than GK until weaning. At 12 and 24 weeks, GK rats were significantly heavier than congenics. RFP weight was significantly higher in congenics than in BN rats (Fig. 1B). As a consequence adiposity index was increased in congenics when compared to BN (Fig. 1C), but this effect was statistically significant (P = 3.3×10−4) in females only (data not shown). Both RFP weight and adiposity index were significantly lower in congenics than in GK rats. Overall these data indicate that GK genetic variants in the congenics account for a proportion of the phenotypic differences between GK and BN rats.

Bottom Line: Complex etiology and pathogenesis of pathophysiological components of the cardio-metabolic syndrome have been demonstrated in humans and animal models.Genotype analysis of single nucleotide polymorphisms (SNPs) in strains genetically related to the GK highlights clusters of conserved and strain-specific variants in RNO1 that can assist the identification of naturally occurring variants isolated in diabetic and hypertensive strains when different phenotype selection procedures were applied.Our results emphasize the importance of rat congenic models for defining the impact of genetic variants in well-characterised QTL regions on in vivo pathophysiological features and cis-/trans- regulation of gene expression.

View Article: PubMed Central - PubMed

Affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

ABSTRACT

Background: Complex etiology and pathogenesis of pathophysiological components of the cardio-metabolic syndrome have been demonstrated in humans and animal models.

Methodology/principal findings: We have generated extensive physiological, genetic and genome-wide gene expression profiles in a congenic strain of the spontaneously diabetic Goto-Kakizaki (GK) rat containing a large region (110 cM, 170 Mb) of rat chromosome 1 (RNO1), which covers diabetes and obesity quantitative trait loci (QTL), introgressed onto the genetic background of the normoglycaemic Brown Norway (BN) strain. This novel disease model, which by the length of the congenic region closely mirrors the situation of a chromosome substitution strain, exhibits a wide range of abnormalities directly relevant to components of the cardio-metabolic syndrome and diabetes complications, including hyperglycaemia, hyperinsulinaemia, enhanced insulin secretion both in vivo and in vitro, insulin resistance, hypertriglyceridemia and altered pancreatic and renal histological structures. Gene transcription data in kidney, liver, skeletal muscle and white adipose tissue indicate that a disproportionately high number (43-83%) of genes differentially expressed between congenic and BN rats map to the GK genomic interval targeted in the congenic strain, which represents less than 5% of the total length of the rat genome. Genotype analysis of single nucleotide polymorphisms (SNPs) in strains genetically related to the GK highlights clusters of conserved and strain-specific variants in RNO1 that can assist the identification of naturally occurring variants isolated in diabetic and hypertensive strains when different phenotype selection procedures were applied.

Conclusions: Our results emphasize the importance of rat congenic models for defining the impact of genetic variants in well-characterised QTL regions on in vivo pathophysiological features and cis-/trans- regulation of gene expression. The congenic strain reported here provides a novel and sustainable model for investigating the pathogenesis and genetic basis of risks factors for the cardio-metabolic syndrome.

Show MeSH
Related in: MedlinePlus