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Abstract
Background: The New Zealand Obese (NZO) mouse is a model of human obesity and type 2 diabetes and therefore suitable for the identification of disease genes by positional cloning. The aim was to identify novel diabetes genes and suppressors in a backcross population of the NZO with the diabetes resistant C57BL/6J (B6) mouse.
Methods: Of the backcross population 600 mice on high-fat diet (45% fat) were intensively phenotyped (body weight and composition, blood glucose, insulin sensitivity) and genotyped for 140 polymorphic SNPs in order to perform linkage analysis for mapping distinct quantitative trait loci (QTL). Recombinant congenic strains (RCS) harbouring the heterozygous locus (NZO/B6) of interest on the NZO genetic background have been characterized in the N4 generation.
Results: NZO-derived diabetogenic QTL (lower total pancreatic insulin and higher blood glucose) were identified on chr.9 (proximal) and 13 (distal). The strongest QTL (LOD 8.5; chr.18) was associated with liver weight, liver fat and blood glucose. Modeling with the program R/qtl suggests the presence of two independent loci mediating opposite effects on blood glucose; one NZO-derived locus is associated with increased liver weight and liver fat and the other NZO-derived locus associates with reduced blood glucose. By studying the RCS we aim to separate these two loci and furthermore to narrow the critical regions for identifying responsible disease genes. For this we will perform sequencing and expression studies in white adipose tissue, muscle and liver of the RCS.
Methods: Of the backcross population 600 mice on high-fat diet (45% fat) were intensively phenotyped (body weight and composition, blood glucose, insulin sensitivity) and genotyped for 140 polymorphic SNPs in order to perform linkage analysis for mapping distinct quantitative trait loci (QTL). Recombinant congenic strains (RCS) harbouring the heterozygous locus (NZO/B6) of interest on the NZO genetic background have been characterized in the N4 generation.
Results: NZO-derived diabetogenic QTL (lower total pancreatic insulin and higher blood glucose) were identified on chr.9 (proximal) and 13 (distal). The strongest QTL (LOD 8.5; chr.18) was associated with liver weight, liver fat and blood glucose. Modeling with the program R/qtl suggests the presence of two independent loci mediating opposite effects on blood glucose; one NZO-derived locus is associated with increased liver weight and liver fat and the other NZO-derived locus associates with reduced blood glucose. By studying the RCS we aim to separate these two loci and furthermore to narrow the critical regions for identifying responsible disease genes. For this we will perform sequencing and expression studies in white adipose tissue, muscle and liver of the RCS.
| Original language | English |
|---|---|
| Article number | P119 |
| Journal | Diabetologie und Stoffwechsel |
| Volume | 10 |
| Issue number | S 01 |
| DOIs | |
| Publication status | Published - 2015 |
| Externally published | Yes |
Research output
- 2 Article
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Identification of Novel Potential Type 2 Diabetes Genes Mediating β-Cell Loss and Hyperglycemia Using Positional Cloning
Aga, H., Hallahan, N., Gottmann, P., Jaehnert, M., Osburg, S., Schulze, G., Kamitz, A., Arends, D., Brockmann, G., Schallschmidt, T., Lebek, S., Chadt, A., Al-Hasani, H., Joost, H. G., Schürmann, A. & Vogel, H., 30 Sept 2020, In: Frontiers in Genetics. 11, 11 p., 567191.Research output: Contribution to journal › Article › peer-review
Open AccessFile8 Citations (Scopus)28 Downloads (Pure) -
Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation
Schwerbel, K., Kamitz, A., Krahmer, N., Hallahan, N., Jähnert, M., Gottmann, P., Lebek, S., Schallschmidt, T., Arends, D., Schumacher, F., Kleuser, B., Haltenhof, T., Heyd, F., Gancheva, S., Broman, K. W., Roden, M., Joost, H. G., Chadt, A., Al-Hasani, H. & Vogel, H. & 2 others, , 1 Oct 2020, In: Journal of Hepatology. 73, 4, p. 771-782 12 p.Research output: Contribution to journal › Article › peer-review
Open AccessFile37 Citations (Scopus)32 Downloads (Pure)