The C57BL/6J Niemann–Pick C1 mouse model with decreased gene dosage has impaired glucose tolerance independent of body weight

The human Niemann–Pick C1 (NPC1) gene has been found to be associated with extreme (early-onset and morbid-adult) obesity and type 2 diabetes independent of body weight. We previously performed growth studies using BALB/cJ Npc1 normal (Npc1+/+) and Npc1 heterozygous (Npc1+/−) mice and determined that decreased Npc1 gene dosage interacts with a high-fat diet to promote weight gain and adiposity. The present study was performed using both BALB/cJ and C57BL/6J Npc1+/+ and Npc1+/− mice to determine if decreased Npc1 gene dosage predisposes to metabolic features associated with type 2 diabetes. The results indicated that C57BL/6J Npc1+/− mice, but not BALB/cJ Npc1+/− mice, have impaired glucose tolerance when fed a low-fat diet and independent of body weight. The results also suggest that an accumulation of liver free fatty acids and hepatic lipotoxicity marked by an elevation in the amount of plasma alanine aminotransferase (ALT) may be responsible for hepatic insulin resistance and impaired glucose tolerance. Finally, the peroxisome-proliferator activated receptor α (PPARα) and sterol regulatory element-binding protein-1 (SREBP-1) pathways known to have a central role in regulating free fatty acid metabolism were downregulated in the livers, but not in the adipose or muscle, of C57BL/6J Npc1+/− mice compared to C57BL/6J Npc1+/+ mice. Therefore, decreased Npc1 gene dosage among two different mouse strains interacts with undefined modifying genes to manifest disparate yet often related metabolic diseases. •The BALB/cJ and C57BL/6J Npc1 mouse models were used.•Decreased Npc1 gene dosage in C57BL/6J mice results in impaired glucose tolerance.•The impaired glucose tolerance is independent of body weight.•The C57BL/6J Npc1+/− mice accumulated free fatty acids in the liver.•Hepatic accumulation of FFA is associated with decreased Pparα and Srebp-1 genes.