Dynamic genetic architecture of metabolic syndrome attributes in the rat

Abstract

The polydactylous rat strain (PD/Cub) is a highly inbred (F Ͼ 90) genetic model of metabolic syndrome. The aim of this study was to analyze the genetic architecture of the metabolic derangements found in the PD/Cub strain and to assess its dynamics in time and in response to diet and medication. We derived a PD/Cub ϫ BN/Cub (Brown Norway) F2 intercross population of 149 male rats and performed metabolic profiling and genotyping and multiple levels of genetic linkage and statistical analyses at five different stages of ontogenesis and after high-sucrose diet feeding and dexamethasone administration challenges. The interval mapping analysis of 83 metabolic and morphometric traits revealed over 50 regions genomewide with significant or suggestive linkage to one or more of the traits in the segregating PD/Cub ϫ BN/Cub population. The multiple interval mapping showed that, in addition to "single" quantitative train loci, there are more than 30 pairs of loci across the whole genome significantly influencing the variation of particular traits in an epistatic fashion. This study represents the first whole genome analysis of metabolic syndrome in the PD/Cub model and reveals several new loci previously not connected to the genetics of insulin resistance and dyslipidemia. In addition, it attempts to present the concept of "dynamic genetic architecture" of metabolic syndrome attributes, evidenced by shifts in the genetic determination of syndrome features during ontogenesis and during adaptation to the dietary and pharmacological influences.quantitative trait loci; pharmacogenetics; nutrigenetics; triglyceride; insulin resistance; obesity METABOLIC SYNDROME is a complex condition arising from an intricate network of interacting genetic and environmental factors. The dynamics of the increase in its worldwide prevalence qualify the syndrome as a major healthcare issue for years to come. The syndrome comprises several clinical features, each representing a complex trait of its kind, i.e., hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, and hypertension (11,36). It is therefore self evident that detailed analysis of the genetic determinants underlying such metabolic clustering is rather complicated in the general human population and only somewhat more feasible in particular circumstances, e.g., in population isolates (32). Although some progress has been made and several studies succeeded in identification of genes potentially involved in the pathogenesis of metabolic syndrome (13,17,35,51), its genetic determination is far from being fully understood.As in other complex diseases, defined animal models of metabolic syndrome are proving to be important tools for deciphering the causative genes and gene-gene and geneenvironment interactions (8). There are numerous rodent strains expressing all or a subset of metabolic syndrome attributes found in humans [e.g., Otsuka Long-Evans Tokushima Fatty rat (16), Goto-Kakizaki rat (10), hereditary hypertriglyceridemic rat (53, 54), and spontaneously hypertensive rat ...

Pharmacogenetic interaction between dexamethasone and Cd36-deficient segment of spontaneously hypertensive rat chromosome 4 affects triacylglycerol and cholesterol distribution into lipoprotein fractions

“…Several genes have been proposed to transduce or modulate the metabolic effects of glucocorticoids, including functional candidates like glucocorticoid receptor [3], 11β-hydroxysteroid dehydrogenases 1 and 2 (11β-HSD1, 2) [4] and corticosteroid-binding globulin (CBG) [5], and peroxisome proliferator-activated receptor alpha (PPARα) [6]. We have previously reported a comprehensive set of quantitative trait loci related to genomic architecture of metabolic syndrome including its dynamics in response to dexamethasone (DEX)-induced derangements of lipid and carbohydrate metabolism [7]. …”

Identification of genetic loci involved in diabetes using a rat model of depression

“…Of particular interest is the number of body weight loci that we identified which overlap with body weight loci previously identified using inbred models of hypertension (Inomata et al 2005; Kovacs et al 1998; Moreno et al 2003; Redina et al 2006), metabolic syndrome (Bilusic et al 2004; Kloting et al 2001; Seda et al 2005) and T2D (Chung et al 1997; Granhall et al 2006; Watanabe et al 1999; Watanabe et al 2001). Furthermore, MC4R , a gene recently identified in human GWAS for obesity (Loos et al 2008), lies within the chromosome 18 QTL.…”

Heterozygous connexin 50 mutation affects metabolic syndrome attributes in spontaneously hypertensive rat

“…Animals had free access to food (standard chow) and water at all times. At 4 months of age, males from the SHR, SHR- Dca +/− and SHR- Dca −/− strains ( n = 8/strain/procedure) were administered dexamethasone (Dexamed, Medochemie) in drinking water (2.6 μg/ml) for three days as described previously [11, 12]. Subsequently, they were subjected to an oral glucose tolerance test (OGTT) after overnight fasting and blood samples were drawn.…”

“…The resulting mutant coisogenic strain SHR-Gja8 m1Cub (SHR- Dca −/− hereafter, RGD ID: 2293729) shows decreased blood pressure compared to SHR [10]. This study aimed to further explore the effects of connexin50 mutation on metabolic and cytokine profile in SHR- Dca −/− and SHR- Dca +/− strains including a battery of parameters of oxidative stress in the animals challenged by dexamethasone, a dyslipidemia and insulin resistance-inducing glucocorticoid [11, 12]. …”