A backcross model of New Zealand obese mice (NZO) with the lean, atherosclerosis-resistant SJL strain was established to locate genes responsible for obesity, insulin resistance, and type 2 diabetes-like hyperglycemia. In male NZO ؋ F1 backcross mice, a major susceptibility locus for the development of hyperglycemia and hypoinsulinemia (Nidd/SJL) was identified on chromosome 4 between the markers D4Mit278 and D4Mit232, 10-28 cM distal of the previously described Nidd1 locus. The diabetogenic allele has presumably been contributed by the SJL genome, and it appeared to be responsible for ~60% of the total prevalence of hyperglycemia. The presence of Nidd/SJL did not alter body weight or weight gain by week 12. Thereafter, it was associated with reduced weight gain or weight loss, presumably as a consequence of decompensated hyperglycemia. In all male backcross mice, the prevalence of hyperglycemia at week 22 increased with the body weight at week 12, suggesting that the development of hyperglycemia was dependent on the degree of obesity. In the absence of Nidd/SJL, mice weighing <50 g at week 12 did not develop hyperglycemia by week 22. In contrast, in animals carrying the diabetogenic allele, the prevalence of hyperglycemia was 20 and 64% when the 12-week weight was <45 and 45-50 g, respectively. These data are consistent with the conclusion that Nidd/SJL represents a diabetes gene that lowers the obesity threshold for the development of hyperglycemia and hypoinsulinemia. Diabetes 49:1590-1596, 2000 N ew Zealand obese (NZO) mice exhibit a polygenic syndrome of hyperphagia, obesity, and insulin resistance (1-5). In the course of the syndrome, some NZO mice develop islet cell failure, hypoinsulinemia, and overt hyperglycemia. Thus, the NZO strain is an ideal model for the identification of the genes that are responsible for aberrations of glucose metabolism and insulin action in mice. Recently, a cross between NZO and NON mice was established, and it was shown that susceptibility loci derived from both NON (Nidd1 and Nidd2) and NZO genomes (Nidd3) contributed to the development of hyperglycemia and hypoinsulinemia (6). Furthermore, it has been shown that leptin resistance might be the primary cause of obesity in NZO mice (7,8). Interestingly, a leptin receptor variant with several amino acid exchanges (Lepr A720T/T1044I ), including 2 nonconservative substitutions (A720T; T1044l), was found in the NZO strain (7). However, the contribution of Lepr A720T/T1044I to the metabolic syndrome of the NZO mouse was unclear, because the allele was also present in the related nonobese New Zealand Black (NZB) strain.To assess the contribution of Lepr A720T/T1044I and identify other susceptibility loci for obesity and insulin resistance, we established a backcross model of NZO mice with the lean and atherosclerosis-resistant SJL strain (9,10). Surprisingly, we found that the prevalence of hyperglycemia and hypoinsulinemia in the male NZO ϫ F1 backcross mice was higher than expected and that this effect was due to a diabetogenic ...
Aims/hypothesis. The diabetes susceptibility locus Nidd/SJL was identified in an outcross of New Zealand obese (NZO) and lean Swiss/Jackson Laboratory mouse strain (SJL) mice. Here we characterise its effects in a NZO × F1(SJL×NZO) backcross population raised on high-fat or standard diet, and describe its interaction with the obesity quantitative trait locus (QTL) Nob1. Methods. NZO × F1(SJL×NZO) backcross mice were raised on a normal or high fat diet and were monitored (body weight, blood glucose, serum insulin) for 22 weeks. Genotypes of polymorphic markers were determined by PCR, and linkage analysis was done. Pancreas morphology was assessed by conventional staining and immunohistochemistry of insulin. Results. In backcross mice raised on a high-fat diet, Nidd/SJL produced hyperglycaemia (maximum likelihood of the odds (LOD) score 9.9), hypoinsulinaemia, reduction of islet-cell volume, and loss of beta cells. No effect was observed on body weight and serum insulin concentrations before the onset of hyperglycaemia. The development of diabetes in carriers of Nidd/SJL was markedly accelerated and aggravated by the obesity/hyperinsulinaemia QTL Nob1; together, these loci were responsible for approximately 90% of the diabetes observed in the backcross population. When raised on a standard diet, Nidd/SJL carriers exhibited a fivefold higher prevalence of diabetes, but Nob1 failed to enhance the effect of Nidd/SJL. Conclusion/interpretation. Diabetes in this obese mouse model is the result of an interaction of genes responsible for obesity/insulin resistance (e.g. Nob1) and islet cell failure (Nidd/SJL). The combined diabetogenic effects of Nidd/SJL and Nob1 were markedly enhanced by a high-fat diet, whereas that of Nidd/SJL alone was independent of the dietary fat content. [Diabetologia (2002) 45:823-830]
New Zealand obese (NZO) mice show a polygenic syndrome of hyperphagia, obesity and insulin resistance [1±3] that resembles the human metabolic syndrome [4]. Thus, the NZO strain is an ideal model for the identification of the genes that are responsible for aberrations of body weight regulation and insulin action in mice. Moreover, the NZO strain has been used to characterize the interaction of obesity and diabetes genes (`diabesity') and to identify diabetes genes from other mouse strains that accelerate the development of hyperglycaemia in NZO mice [5].It has previously been suggested that leptin resistance is a primary cause of the obesity in NZO mice [3,6]. Notably, a leptin receptor variant with four amino-acid exchanges including two non-conservative substitutions (A720T, T1044I; Lepr A720T/T1044I ) was found in the NZO strain [3]. The contribution of Lepr A720T/T1044I to the metabolic syndrome of the NZO mouse was, however, not clear because the allele was also present in the related non-obese New Zealand Black (NZB) strain.To further assess the contribution of Leprand identify other susceptibility loci for obesity and insulin resistance, we established a backcross model Diabetologia (2000)
New Zealand obese (NZO) mice exhibit severe insulin resistance of hepatic glucose metabolism. In order to define its biochemical basis, we studied the differential expression of genes involved in hepatic glucose and lipid metabolism by microarray analysis. NZO×F1 (SJL×NZO) backcross mice were generated in order to obtain populations with heterogeneous metabolism but comparable genetic background. In these backcross mice, groups of controls (normoglycemic/normoinsulinemic), insulin-resistant (normoglycemic/ hyperinsulinemic) and diabetic (hyperglycemic/hypoinsulinemic) mice were identified. At 22 weeks, mRNA was isolated from liver, converted to cDNA, and used for screening of two types of cDNA arrays (high-density filter arrays and Affymetrix oligonucleotide microarrays). Differential gene expression was ascertained and assessed by Northern blotting. The data indicate that hyperinsulinemia in the NZO mouse is associated with: (i) increased mRNA levels of enzymes involved in lipid synthesis (fatty acid synthase, malic enzyme, stearoyl-CoA desaturase) or fatty acid oxidation (cytochrome P450 4A14, ketoacyl-CoA thiolase, acyl-CoA oxidase), (ii) induction of the key glycolytic enzyme pyruvate kinase, and (iii) increased mRNA levels of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase. These effects were enhanced by a high-fat diet. In conclusion, the pattern of gene expression in insulin-resistant NZO mice appears to reflect a dissociation of the effects of insulin on genes involved in glucose and lipid metabolism. The data are consistent with a hypothetical scenario in which an insulin-resistant hepatic glucose production produces hyperinsulinemia, and an enhanced insulin-and substrate-driven lipogenesis further aggravates the deleterious insulin resistance of glucose metabolism.
In subgroups of a New Zealand obese mouse-derived backcross population with defined aberrations of glucose homeostasis, a comprehensive study of the hepatic expression of cytochrome P450 and glutathione S-transferase was performed. Three patterns of alterations in response to insulin resistance (normoglycemia/hyperinsulinemia) or diabetes (hyperglycemia/hypoinsulinemia) were observed: mRNA levels of Cyp2b9, Cyp3a16, Cyp4a14, and Gstt2 as assessed by Northern-and dot-blot analysis were increased markedly in liver from diabetic mice with no or only a slight increase in insulin resistant mice. Western-blot analysis detected the corresponding changes of the CYP2B and CYP4A proteins. In contrast, expression of Cyp2c22, Cyp2c29, and Cyp2c40 was reduced in diabetic, but normal in insulin resistant mice. These alterations were correlated with changes in serum free fatty acid levels and, therefore, seem to be mediated by the peroxisome proliferator activated receptor-␣. Furthermore, expression of Cyp1a2, Cyp7b1, Gstm3, and Gstm6 was reduced in both diabetic and insulin resistant mice. Because this third pattern was not correlated with the alterations of serum free fatty acid levels, it seems to reflect an early alteration in the course of the disease, and may be related to the progression of the syndrome from insulin resistance to the type 2-like diabetes.New Zealand obese (NZO) mice exhibit a polygenic syndrome of obesity, insulin resistance, dyslipidemia, and hypertension that is similar to the human metabolic syndrome . Like other rodents with morbid obesity, the strain exhibits impaired glucose tolerance and eventually develops a type 2 diabetes-like hyperglycemia and hypoinsulinemia. Thus, the NZO mouse is a suitable model for the identification of obesity and diabetes genes and for the characterization of their interaction (Leiter et al., 1998;.We have recently established a backcross model of NZO mice with the lean and atherosclerosis-resistant SJL strain . The male NZO ϫ F1 (SJL ϫ NZO) backcross population (referred to as NSZO) is heterogeneous and includes normoglycemic/normoinsulinemic animals, insulin resistant animals with a compensatory hyperinsulinemia, and diabetic animals with hyperglycemia/hypoinsulinemia. This heterogeneity defines different stages in the development of diabetes and reflects the different genetic burden of the subgroups. A striking characteristic of the backcross is that only a few female mice develop hypoinsulinemia, despite a marked obesity and hyperinsulinemia. In a genome-wide scan of the NSZO backcross population, we identified a susceptibility locus for obesity/hyperinsulinemia and a separate locus for hyperglycemia/ hypoinsulinemia that was contributed by the SJL genome ; together, these loci are responsible for approximately 90% of the prevalence of diabetes in the backcross. In addition to the genome-wide search for disease susceptibility loci, we have used the NSZO backcross population for
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