JAX Notes October 01, 2002

Polygenic obesity mouse models

Although excellent mouse models of monogenic obesity syndromes are available, including leptin (Lepob [obese]) and leptin receptor (Leprdb [diabetic]) strains, 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 Edward Leiter, Ph.D., and Senior Research Assistant 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 that 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.

Table 1. Phenotypic characteristics of 10 recombinant congenic strains (RCS). Male mice were maintained on an NIH-31 diet with 6% fat content (LabDiet® 5K52) from weaning until data collection.

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/HlLtJ

20% (2/10)

50% (5/10)

55.6

34.5 + 4.5

71.8 + 3.8

NON/ShiLtJ

0% (0/21)

0% (0/21)

34

1.5 + 0.3

11.6 + 2.1

NONcNZO1/Lt

35% (7/20)

50% (10/20)

38.2

6.2 + 2.8

29.2 + 4.1

NONcNZO2/Lt

5% (1/22)

32% (7/22)

37.7

1.4 + .4

11.2 + 2.2

NONcNZO3/Lt

0% (0/9)

0% (0/9)

45.9

16.0 + 5.8

34.2 + 5.4

NONcNZO4/Lt

0% (0/10)

0% (0/10)

37.1

5.2 + 1.0

28.4 + 12.3

NONcNZO5/LtJ

0% (0/12)

0% (0/12)

40.4

5.5 + .5

28.2 + 3.2

NONcNZO6/Lt

20% (4/20)

45% (9/20)

40.7

4.1 + 0.7

11.3 + 2.6

NONcNZO7/Lt

22% (2/9)

33% (3/9)

43.7

11.7 + 2.9

9.7 + 1.9

NONcNZO8/Lt

13% (2/15)

67% (10/15)

44.4

13.5 + 2.4

20.3 + 3.1

NONcNZO9/Lt

10% (1/10)

 30% (3/10)

43.6

9.8 + 1.9

8.4 + 2.2

NONcNZO10/LtJ

79% (22/28)

86% (24/28)

41

7.1 + .8

23.2 + 3.5

References

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. Lipid metabolome-wide effects of the peroxisome proliferator-activated receptor gamma rosiglitazone on a new mouse model of type 2 diabetes. J. Lipid Res 2002 Nov; 43(11):1809-17.