Diet-induced obesity in two C57BL/6 substrains with intact or mutant nicotinamide nucleotide transhydrogenase (Nnt) gene

Abstract

The C57BL/6J (B6/J) male mouse represents a standard for diet-induced obesity (DIO) and is unique in expressing a loss-of-function nicotinamide nucleotide transhydrogenase (Nnt) gene. This mutation was associated with a marked reduction in glucose-stimulated insulin secretion from B6/J islets in vitro and moderately impaired glucose clearance in vivo. To assess the contribution of this Nnt mutation, we compared DIO responsiveness of Nnt-mutant B6/J males to Nnt wild-type C57BL/6NJ (B6/NJ) males over a 14-week period of feeding a high-fat (60% of calories) diet. Initial mean body weights at 6 weeks did not distinguish the substrains and both substrains were DIO-sensitive. However, B6/J males outgained the B6/NJ males, with a significant 3 g higher mean body weight at 20 weeks accompanied by significant increases in both lean and fat mass. Mean nonfasting serum glucose over time was also significantly higher in B6/J males, as was impairment of glucose tolerance assessed at 8 and 20 weeks of age. Serum leptin, but not insulin, was significantly higher in B6/J males over time. Potential contributions of the wild-type Nnt gene were demonstrable on a lower fat diet (10% of calories) where a significantly greater weight gain over time by B6/NJ males was correlated with a significantly higher serum insulin. In conclusion, DIO developed in response to 60% fat feeding regardless of Nnt allele status. Contribution of the B6/J-unique Nnt mutation was most evident in response to 10% fat feeding that resulted in reduced serum insulin and weight gain compared to B6/NJ males.

Keywords: Adiposity; Animal Models; Dietary Fat; Genetics; Insulin Secretion.

Figure 1

Greater rate of weight gain in a cohort of 40 B6/J males compared to 39 B6/NJ males fed 60% fat diet from 6–20 weeks of age (P<0.0001). Note comparable starting weights.

Figure 2

Severe impairment of glucose tolerance in both substrains after 2 weeks (A) and 14 weeks (B) of feeding 60% fat diet, but with greater impairment in B6/J males (P<0.0001).

Figure 3

Greater weight gain of a cohort of 30 B6/NJ males compared to 30 B6/J males fed the 10% fat diet from 6–20 weeks of age (P<0.0001). Note the reciprocal nature of the substrain response compared to that on the 60% fat diet shown in Figure 1.