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

Jun 18, 2013Gene

Reduced Niemann-Pick C1 gene causes poor glucose tolerance in C57BL/6J mice regardless of body weight

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Abstract

C57BL/6J Npc1+/- mice exhibited impaired glucose tolerance when fed a low-fat diet.

Decreased dosage of the Npc1 gene is linked to metabolic features associated with type 2 diabetes.
Impaired glucose tolerance occurred independently of body weight in C57BL/6J Npc1+/- mice.
An accumulation of liver free fatty acids and elevated plasma alanine aminotransferase (ALT) may indicate hepatic insulin resistance.
Downregulation of pathways involved in free fatty acid metabolism was observed in the livers of C57BL/6J Npc1+/- mice compared to Npc1+/+ mice.
Disparate metabolic disease manifestations may arise from decreased Npc1 gene dosage interacting with unknown modifying genes.

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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.

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

Abstract

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