Influence of Nnt alleles on DIO in C57BL/6 JAX® Mice
JAX® NOTES Issue 511, Fall 2008
If you research diabetes and/or obesity you may be wondering if the null mutation of the NAD nucleotide transhydrogenase (Nnt) gene (Toye et al. 2005; Freeman et al. 2006) in JAX® Mice strain C57BL/6J (B6/J, 000664) affects its responsiveness to diet-induced obesity (DIO). The answer is "No". JAX scientist Dr. Edward Leiter recently compared the Nnt allele's effects on DIO responsiveness in Nnt-mutant B6/J males to C57BL6/NJ males (B6/NJ, 005304), which have the wild-type Nnt allele (unpublished research, The Jackson Laboratory) (Leiter 2008).
Cohorts of 40 six-week-old males from both substrains were fed a semi-defined diet containing 60% of its calories as fat (Research Diets D12492) for 14 weeks. The initial mean body weight (BW) of both cohorts did not differ (Figure 1), but, during the 14 weeks, the B6/J males significantly outgained the B6/NJ males, and, at the end of the study, weighed an average of 4g more than the B6/NJ males. Dual emission X-ray absorptiometry (DEXA) showed that this difference was due to a significantly higher lean and fat mass in B6/J males (Table 1). Mean non-fasting plasma glucose (PG) levels were also significantly higher in the B6/J males (sampled in eight, 12, 16, and 20-week-old mice).
Glucose tolerance became progressively more impaired in both substrains, but was significantly more severe in the B6/J substrain (Figure 2). Mean plasma insulin (PI) levels in 20-week-old mice were modestly (but not significantly) higher in B6/NJ males, consistent with their less severe IGT response (Table 1). Consistent with the greater adiposity of B6/J mice, mean plasma leptin (PL) levels were modestly higher in 20-week-old B6/J males and significantly higher in these males over time than in B6/NJ males (Table 1).
In summary, Dr. Leiter’s study revealed that B6/J males had a significantly more robust DIO response (higher weight gain, more adiposity, and more severe IGT) than B6/NJ males. Homozygosity for the Nnt mutation did not diminish male B6/J responsiveness to a 60% kcal fat diet. We cannot conclude that the mutant B6/J Nnt allele is the factor responsible for the more robust DIO response because certain strains that are even more DIO-responsive than B6/J, such as NON/ShiLtJ (002423), are Nnt wild-type (JAX® NOTES 2006). Likewise, strains such as A/J (000646), which are DIO-resistant (Surwit et al. 1988), are also Nnt wild-type (Freeman et al. 2006 supplemental material). As in humans, glucose homeostasis in these inbred strains is controlled by multiple genes.
Table 1. Comparative DIO phenotypes of 20-week-old B6/J and B6/NJ males fed a semi-defined diet containing 60% of its calories as fat (Research Diets D12492) for 14 weeks, from six to 20 weeks old (Data show mean ± SEMa).
| Substrain | PG (mg/dl) | BW (g) | Lean Tissue (g) | Fat Tissue (g) | Percent Fat | PI (ng/ml) | PL (ng/ml) |
| B6/J | 237 ± 5b | 45.4 ± 0.4 b | 22.5 ± 0.5c | 20.6 ± 1.1c | 46.4 | 8.9 ± 1.3 | 90.1 ± 5.3 |
| B6/NJ | 198 ± 5 | 41.2 ± 0.4 | 20.8 ± 0.5 | 16.3 ± 1.1 | 44.0 | 10.7 ± 3.1 | 72.4 ± 8.5 |
a n = 39-40/group for PG and BW, 12/group for DEXA parameters, and 10/group for plasma analytes
b Substrain differences significant at P < 0.0001 (statistical comparisons by JMP ANOVA program)
c Substrain differences significant at P = 0.03 (statistical comparisons by JMP ANOVA program)
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Figure 1. B6/J males had a significantly more rapid DIO response than B6/NJ males (n = 39-40/group, P < 0.0001 by |
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| Figure 2. Glucose tolerance was significantly more impaired in B6/J than in B6/NJ males after groups of each had been fed a 60% kcal fat diet for two and 14 weeks (n = 12/group, P = 0.03) | |
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References
(Author in bold is a Jackson Laboratory scientist.)
Freeman HC, Hugill A, Dear NT, Ashcroft FM. Cox RD. 2006. Deletion of nicotinamide nucleotide transhydrogenase; a new quantitative trait locus accounting for glucose intolerance in C57BL/6J mice. Diabetes 55:2153-6.
JAX® NOTES. 2006. NON/LtJ Males: a new model of diet-induced diabesity. JAX® NOTES 503:4.
Leiter EH. 2008. Does a mutant NAD nucleotide transhydrogenase (Nnt) gene in C57BL/6J impair responsiveness to diet-induced obesity? The Jackson Laboratory.
Surwit RS, Kuhn CM, Cochrane C, McCubbin JA Feinglos MN. 1988. Diet-Induced type 2 diabetes in C57BL/6J mice. Diabetes 37:1163-7.
Toye AA, Lippiat JD, Proks P, Shimomura K, Bentley L, Hugill A, Mijat V, Goldsworthy M, Moir L, Haynes A, Quarterman J, Freeman HC Ashcroft FM, Cox RD. 2005. A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice. Diabetologia 48:675-86
