CD36-deficient congenic strains show improved glucose tolerance and distinct shifts in metabolic and transcriptomic profiles

Šedová, Lucie; Liška, František; Křenová, D; Kazdová, Ludmila; Tremblay, Johanne; Krupková, Michaela; Corbeil, Gilles; Hamet, Pavel; Křen, Vladimı́r; Šeda, Ondřej

doi:10.1038/hdy.2012.14

Cited by 6 publications

(4 citation statements)

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“…Blood samples for glycemic assessment (Ascensia Elite Blood Glucose Meter, Bayer HealthCare, Mishawaka, IN, USA; validated by the Institute of Clinical Biochemistry and Laboratory Diagnostics of the First Faculty of Medicine, Charles University in Prague) were obtained from the tail vein at intervals of 0, 30, 60, 120, and 180 min after intragastric glucose administration to conscious rats (3 g/kg body weight, 30% aqueous solution). The lipid profile (cholesterol and triacylglycerols blood concentration in 20 lipoprotein fractions, glycerol level and chylomicron, VLDL, LDL and HDL particle sizes) was assessed by high performance liquid chromatography method as described previously [13, 14]. Enzyme-linked immunosorbent assay (ELISA) kits were used to determine the serum levels of adiponectin (BioSource, San Diego, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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BackgroundSeveral members of connexin family of transmembrane proteins were previously implicated in distinct metabolic conditions. In this study we aimed to determine the effects of complete and heterozygous form of connexin50 gene (Gja8) mutation L7Q on metabolic profile and oxidative stress parameters in spontaneously hypertensive inbred rat strain (SHR).MethodsAdult, standard chow-fed male rats of SHR, heterozygous SHR-Dca+/− and SHR-Dca−/− coisogenic strains were used. At the age of 4 months, dexamethasone (2.6 μg/ml) was administered in the drinking water for three days. The lipidemic profile (cholesterol and triacylglycerol concentration in 20 lipoprotein fractions, chylomicron, VLDL, LDL and HDL particle sizes) together with 33 cytokines and hormones in serum and several oxidative stress parameters in plasma, liver, kidney and heart were assessed.ResultsSHR and SHR-Dca−/− rats had similar concentrations of triacylglycerols and cholesterol in all major lipoprotein fractions. The heterozygotes reached significantly highest levels of total (SHR-Dca+/−: 51.3 ± 7.2 vs. SHR: 34.5 ± 2.4 and SHR-Dca−/−: 34.4 ± 2.5 mg/dl, p = 0.026), chylomicron and VLDL triacylglycerols. The heterozygotes showed significantly lowest values of HDL cholesterol (40.9 ± 2.3 mg/dl) compared both to SHR (51.8 ± 2.2 mg/dl) and SHR-Dca−/− (48.6 ± 2.7 mg/dl). Total and LDL cholesterol in SHR-Dca+/− was lower compared to SHR. Glucose tolerance was improved and insulin concentrations were lowest in SHR-Dca−/− (1.11 ± 0.20 pg/ml) in comparison with both SHR (2.32 ± 0.49 pg/ml) and SHR-Dca+/− (3.04 ± 0.21 pg/ml). The heterozygous rats showed profile suggestive of increased oxidative stress as well as highest serum concentrations of several pro-inflammatory cytokines including interleukins 6, 12, 17, 18 and tumor necrosis factor alpha.ConclusionsOur results demonstrate that connexin50 mutation in heterozygous state affects significantly the lipid profile and the oxidative stress parameters in the spontaneously hypertensive rat strain.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-016-0376-3) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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“…1641851) strains were maintained at the Institute of Medical Biology and Genetics, Charles University in Prague. To derive SHR- Lx .PD5 PD- Zbtb16 and SHR- Lx .PD5 SHR- Zbtb16 congenic strains, a marker-assisted backcross breeding approach was used, as described previously ( 12 , 22 , 23 ). In short, SHR rats were crossed with SHR- Lx .PD5 rats, and the subsequent F1 hybrids were repeatedly backcrossed to SHR.…”

Section: Methodsmentioning

confidence: 99%

Single-Gene Congenic Strain Reveals the Effect of Zbtb16 on Dexamethasone-Induced Insulin Resistance

et al. 2018

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BackgroundGlucocorticoids (GCs) are potent therapeutic agents frequently used for treatment of number of conditions, including hematologic, inflammatory, and allergic diseases. Both their therapeutic and adverse effects display significant interindividual variation, partially attributable to genetic factors. We have previously isolated a seven-gene region of rat chromosome 8 sensitizing to dexamethasone (DEX)-induced dyslipidemia and insulin resistance (IR) of skeletal muscle. Using two newly derived congenic strains, we aimed to investigate the effect of one of the prime candidates for this pharmacogenetic interaction, the Zbtb16 gene.MethodsAdult male rats of SHR-Lx.PD5PD-Zbtb16 (n = 9) and SHR-Lx.PD5SHR-Zbtb16 (n = 8) were fed standard diet (STD) and subsequently treated with DEX in drinking water (2.6 µg/ml) for 3 days. The morphometric and metabolic profiles of both strains including oral glucose tolerance test, triacylglycerols (TGs), free fatty acids, insulin, and C-reactive protein levels were assessed before and after the DEX treatment. Insulin sensitivity of skeletal muscle and visceral adipose tissue was determined by incorporation of radioactively labeled glucose.ResultsThe differential segment of SHR-Lx.PD5SHR-Zbtb16 rat strain spans 563 kb and contains six genes: Htr3a, Htr3b, Usp28, Zw10, Tmprss5, and part of Drd2. The SHR-Lx.PD5PD-Zbtb16 minimal congenic strain contains only Zbtb16 gene on SHR genomic background and its differential segment spans 254 kb. Total body weight was significantly increased in SHR-Lx.PD5PD-Zbtb16 strain compared with SHR-Lx.PD5SHR-Zbtb16, however, no differences in the weights of adipose tissue depots were observed. While STD-fed rats of both strains did not show major differences in their metabolic profiles, after DEX treatment the SHR-Lx.PD5PD-Zbtb16 congenic strain showed increased levels of TGs, glucose, and blunted inhibition of lipolysis by insulin. Both basal and insulin-stimulated incorporation of radioactively labeled glucose into skeletal muscle glycogen were significantly reduced in SHR-Lx.PD5PD-Zbtb16 strain, but the insulin sensitivity of adipose tissue was comparable between the two strains.ConclusionThe metabolic disturbances including impaired glucose tolerance, dyslipidemia, and IR of skeletal muscle observed after DEX treatment in the congenic SHR-Lx.PD5PD-Zbtb16 reveal the Zbtb16 locus as a possible sensitizing factor for side effects of GC therapy.

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“…61117) [ 11 ] strains were maintained at the Institute of Medical Biology and Genetics, Charles University in Prague. To derive the SHR.BN16 congenic strain, a marker-assisted backcross breeding approach was used, as described previously [ 11 , 24 , 25 ]. In short, SHR rats were crossed with BN- Lx /Cub rats and the subsequent F1 hybrids were repeatedly backcrossed to SHR/OlaIpcv.…”

Section: Methodsmentioning

confidence: 99%

Isolation of a Genomic Region Affecting Most Components of Metabolic Syndrome in a Chromosome-16 Congenic Rat Model

et al. 2016

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Metabolic syndrome is a highly prevalent human disease with substantial genomic and environmental components. Previous studies indicate the presence of significant genetic determinants of several features of metabolic syndrome on rat chromosome 16 (RNO16) and the syntenic regions of human genome. We derived the SHR.BN16 congenic strain by introgression of a limited RNO16 region from the Brown Norway congenic strain (BN-Lx) into the genomic background of the spontaneously hypertensive rat (SHR) strain. We compared the morphometric, metabolic, and hemodynamic profiles of adult male SHR and SHR.BN16 rats. We also compared in silico the DNA sequences for the differential segment in the BN-Lx and SHR parental strains. SHR.BN16 congenic rats had significantly lower weight, decreased concentrations of total triglycerides and cholesterol, and improved glucose tolerance compared with SHR rats. The concentrations of insulin, free fatty acids, and adiponectin were comparable between the two strains. SHR.BN16 rats had significantly lower systolic (18–28 mmHg difference) and diastolic (10–15 mmHg difference) blood pressure throughout the experiment (repeated-measures ANOVA, P < 0.001). The differential segment spans approximately 22 Mb of the telomeric part of the short arm of RNO16. The in silico analyses revealed over 1200 DNA variants between the BN-Lx and SHR genomes in the SHR.BN16 differential segment, 44 of which lead to missense mutations, and only eight of which (in Asb14, Il17rd, Itih1, Syt15, Ercc6, RGD1564958, Tmem161a, and Gatad2a genes) are predicted to be damaging to the protein product. Furthermore, a number of genes within the RNO16 differential segment associated with metabolic syndrome components in human studies showed polymorphisms between SHR and BN-Lx (including Lpl, Nrg3, Pbx4, Cilp2, and Stab1). Our novel congenic rat model demonstrates that a limited genomic region on RNO16 in the SHR significantly affects many of the features of metabolic syndrome.

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CD36-deficient congenic strains show improved glucose tolerance and distinct shifts in metabolic and transcriptomic profiles

Cited by 6 publications

References 36 publications

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

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

Single-Gene Congenic Strain Reveals the Effect of Zbtb16 on Dexamethasone-Induced Insulin Resistance

Isolation of a Genomic Region Affecting Most Components of Metabolic Syndrome in a Chromosome-16 Congenic Rat Model

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