title: 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Nicholson
authors.forename: Peter C
authors.initials: PC
authors.lastname: Reifsnyder
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Malcolm
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Lucas
authors.forename: Grant R
authors.initials: GR
authors.lastname: MacGregor
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
authors.forename: Edward H
authors.initials: EH
authors.lastname: Leiter
mesh_terms: D000273:Adipose Tissue; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001825:Body Fluid Compartments; D001835:Body Weight; D004032:Diet / Q000009:adverse effects; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D018149:Glucose Intolerance; D007328:Insulin / Q000097:blood*; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009250:NADP Transhydrogenases / Q000235:genetics*; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D015430:Weight Gain
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D020738:Leptin; D009250:NADP Transhydrogenases