New Polygenic Obesity Mouse Models
JAX® NOTES Issue 487, Fall 2002
Although excellent mouse models of monogenic obesity syndromes are available, including leptin (Lepob [obese]) and leptin receptor (Leprdb [diabetes]) lines, most obesity and obesity-associated type 2 diabetes in humans represent contributions from multiple genes. New Zealand Obese (NZO/HlLt) mice represent a model of polygenic obesity and male sex-limited type 2 diabetes. Although they have normal leptin and leptin receptor genes, NZO/HlLt mice exhibit a defect in leptin transport across the blood-brain barrier. Unfortunately, difficulties in breeding NZO/HlLt mice limit their availability and utility.
To circumvent this problem, Jackson Laboratory Senior Staff Scientist Dr. Edward Leiter and Peter Reifsnyder, have developed a series of ten recombinant congenic strains (RCS) that are ideal tools for the genetic dissection and modeling of human diabetogenic obesity syndromes ("diabesity"). The NON/Lt inbred strain background was chosen as a recipient for variable numbers of known quantitative trait loci (QTL) for obesity and diabetes contributed by NZO/HlLt. The NON/Lt background was selected for high fasting blood glucose levels, a low glucose-stimulated insulin release, and a genome which interacts deleteriously with the NZO/HlLt genome to exacerbate diabesity development in F1 males.
Data in Table 1 profiles the phenotypic characteristics of the ten NONcNZO strains. Each strain represents a different mixture of obesity/diabesity contributions from NON/Lt and NZO/HlLt. None of the RCS gain weight as rapidly or become as obese as parental NZO/HlLt males, but all strains weigh significantly more than the parental NON/Lt males.
As has proven the case with other rodent models of diabesity, the hyperglycemia in NZO and (NZOxNON)F1 diabetic males is efficiently treated by the thiazolidinedione class of insulin sensitizing drugs. However, both strains exhibit an unusual sensitivity to thiazolidinedione-enhanced hepatic lipidosis. Because different NZO genomic intervals have been isolated in the RCS, this RCS panel should prove particularly useful for pharmacogenetic testing of anti-diabetic and anti-obesity drugs.
The current genome-wide scan profiles for all ten NONcNZO strains can be viewed at Dr. Leiter's Web site (http://www.jax.org/staff/leiter/labsite/type2_genomics.html).
All ten NONcNZO RCS strains are available in limited quantities from Dr. Leiter's private research colony. Larger colonies of the diabetes-resistant NONcNZO5 (Stock Number 003672) and diabetes susceptible NONcNZ010 (Stock Number 003859) are currently under development and will become available for distribution in the coming months. Interest in these strains can be registered from the JAX® Mice Database.
Figure 1. Compares rate of weight gain in NONcNZ05 (NcZ5), a diabetes-free but relatively obese RCS with that of NONcNZO10 (NcZ10), a line with 86-100% diabesity development between 12-24 weeks of age. For investigators interested in testing an obesity syndrome complicated or uncomplicated with diabesity development, this strain pairing would be useful because the two strains are relatively well-matched for body weights.
|
Type II Diabetes Incidence |
Body Weight |
Insulin |
Leptin | ||
|
Strain |
% by 20 weeks |
% by 24 weeks |
16 weeks (g) |
24 weeks (ng/ml) |
24 weeks (ng/ml) |
| (NZOxNON)F1 | 97% (29/30) | 97% (29/30) | 55.9 | 9.7 + 4.3 | 54.6 + 5.4 |
| NZO/HlLt | 20% (2/10) | 50% (5/10) | 55.6 | 34.5 + 4.5 | 71.8 + 3.8 |
| NON/Lt | 0% (0/21) | 0% (0/21) | 34 | 1.5 + 0.3 | 11.6 + 2.1 |
| NONcNZO1 | 35% (7/20) | 50% (10/20) | 38.2 | 6.2 + 2.8 | 29.2 + 4.1 |
| NONcNZO2 | 5% (1/22) | 32% (7/22) | 37.7 | 1.4 + .4 | 11.2 + 2.2 |
| NONcNZO3 | 0% (0/9) | 0% (0/9) | 45.9 | 16.0 + 5.8 | 34.2 + 5.4 |
| NONcNZO4 | 0% (0/10) | 0% (0/10) | 37.1 | 5.2 + 1.0 | 28.4 + 12.3 |
| NONcNZO5 | 0% (0/12) | 0% (0/12) | 40.4 | 5.5 + .5 | 28.2 + 3.2 |
| NONcNZO6 | 20% (4/20) | 45% (9/20) | 40.7 | 4.1 + 0.7 | 11.3 + 2.6 |
| NONcNZO7 | 22% (2/9) | 33% (3/9) | 43.7 | 11.7 + 2.9 | 9.7 + 1.9 |
| NONcNZO8 | 13% (2/15) | 67% (10/15) | 44.4 | 13.5 + 2.4 | 20.3 + 3.1 |
| NONcNZO9 | 10% (1/10) | 30% (3/10) | 43.6 | 9.8 + 1.9 | 8.4 + 2.2 |
| NONcNZO10 | 79% (22/28) | 86% (24/28) | 41 | 7.1 + .8 | 23.2 + 3.5 |
Table 1. Phenotyic Characteristics of the 10 RCS. All data collected comes from males maintained from weaning on an NIH-31 diet with 6% fat content (LabDiet® 5K52).
References
(authors in bold are Jackson Laboratory Scientists)
Reifsnyder PC and Leiter EH. Deconstructing and reconstructing obesity-induced diabetes (diabesity) in mice. Diabetes 2002; 51:825-832.
Watkins SM, Reifsnyder PR, Pan HJ, German B, Leiter EH. 200_. Lipid metabolome-wide effects of the peroxisome proliferator-activated receptor gamma rosiglitazone on a new mouse model of type 2 diabetes. J. Lipid Res., in press.
