CD36-DEFICIENT CONGENIC STRAINS SHOW IMPROVED GLUCOSE TOLERANCE AND DISTINCT SHIFTS IN METABOLIC AND TRANSCRIPTOMIC PROFILES

ABSTRACT: Deficiency of fatty acid translocase Cd36 has been shown to play major role in pathogenesis of metabolic syndrome components in the spontaneously hypertensive rat (SHR). We have tested the hypothesis that effects of Cd36 mutation on 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 defective Cd36 gene, into genetic background of highly inbred model of insulin resistance and dyslipidemia, polydactylous (PD) rat strain. We have subjected standard diet-fed adult males of PD and the 2 congenic PD.SHR4 strains to metabolic, morphometric and transcriptomic (Affymetrix Rat 1.0 ST Exon array) profiling. We observed significantly improved glucose tolerance and lower fasting insulin in PD.SHR4 congenics than in PD. One of the PD.SHR4 strains also showed lower triglyceride concentrations across major lipoprotein fractions combined with higher concentrations of LDL cholesterol compared to PD progenitor. The other PD.SHR4 strain had lower total and HDL cholesterol as well as lower LDL and HDL triacylglycerol content compared to PD. The hepatic transcriptome assessment revealed network of genes differentially expressed between PD and PD.SHR4 with significant enrichment by members of circadian rhythmicity pathway (Arntl (Bmal1), Clock, Nfil3, Per2 and Per3). In summary, the introduction of chromosome .4 region of SHR origin including defective Cd36 into 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 indicate that the eventual metabolic effect of deleterious mutation such as that of SHR-derived Cd36 is not absolute, but rather a function of complex interactions between environment and genomic background, upon which it operates. Affymetrix GeneChip® Rat Exon 1.0 ST Array was used to determine the transcriptomic characteristics of the PD.SHR4a and the progenitor PD strain. We extracted total RNA from the liver of 4-month-old males of both strains (n=8/per strain) using phenol-chloroform and purified with the RNeasy Mini kit (Qiagen) in accordance with the manufacturer’s protocol. The quality of the total RNA was verified by the Agilent 2100 Bioanalyzer system. Double-stranded complementary DNA (cDNA) was synthesized from total RNA. The labeled and fragmented cDNA was pooled for each strain and hybridized to Affymetrix GeneChip® Rat Exon 1.0 ST Arrays (PD.SHR4a - 2 chips; PD - 3 chips). The whole hybridization procedure including DNA adjustment was performed according to the protocol recommended by Affymetrix.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Ondrej Seda 

PROVIDER: E-GEOD-33597 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress