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Several corresponding regions of human and mammalian genomes have been shown to affect sensitivity to the manifestation of metabolic syndrome via nutrigenetic interactions. In this study, we assessed the effect of sucrose administration in a newly established congenic strain BN.SHR20, in which a limited segment of rat chromosome 20 from a metabolic syndrome model, spontaneously hypertensive rat (SHR), was introgressed into Brown Norway (BN) genomic background. We mapped the extent of the differential segment and compared the genomic sequences of BN vs. SHR within the segment in silico. The differential segment of SHR origin in BN.SHR20 spans about 9 Mb of the telomeric portion of the short arm of chromosome 20. We identified non-synonymous mutations e.g., in ApoM, Notch4, Slc39a7, Smim29 genes and other variations in or near genes associated with metabolic syndrome in human genome-wide association studies. Male rats of BN and BN.SHR20 strains were fed a standard diet for 18 weeks (control groups) or 16 weeks of standard diet followed by 14 days of high-sucrose diet (HSD). We assessed the morphometric and metabolic profiles of all groups. Adiposity significantly increased only in BN.SHR20 after HSD. Fasting glycemia and the glucose levels during the oral glucose tolerance test were higher in BN.SHR20 than in BN groups, while insulin levels were comparable. The fasting levels of triacylglycerols were the highest in sucrose-fed BN.SHR20, both compared to the sucrose-fed BN and the control BN.SHR20. The non-esterified fatty acids and total cholesterol concentrations were higher in BN.SHR20 compared to their respective BN groups, and the HSD elicited an increase in non-esterified fatty acids only in BN.SHR20. In a new genetically defined model, we have isolated a limited genomic region involved in nutrigenetic sensitization to sucrose-induced metabolic disturbances.

Background: Glucocorticoids 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 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. Methods. Adult 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 three days. The morphometric and metabolic profiles of both strains including oral glucose tolerance test, triacylglycerols, 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 labelled glucose. Results. The differential segment of SHR-Lx.PD5SHR-Zbtb16 rat strain spans 563kb 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 254kb. Total body weight was significantly increased in SHR-Lx.PD5PD-Zbtb16 strain compared to 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 triacylglycerols, 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. Conclusion. The metabolic disturbances including impaired glucose tolerance, dyslipidemia and insulin resistance 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 glucocorticoid therapy.

Background Glucocorticoids (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. Methods Adult 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. Results The 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. Conclusion The 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.