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

Abstract

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 amino-transferase (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.

Differential Association of Niemann-Pick C1 Gene Polymorphisms with Maternal Prepregnancy Overweight and Gestational Diabetes

“…Specifically, the derived and major allele for 1926C>G encoding the I642M residue was associated (OR 2.10, 95% CI 1.11-3.96, P = 0.022) with maternal prepregnancy overweight (BMI 25.0-29.9kg/m 2 ) while the ancestral and major allele for 2572A>G encoding the I858V residue was associated (OR 4.68, 95% CI 1.23-17.8, P = 0.024) with gestational diabetes in non-Hispanic whites, but not Hispanics or Native Americans. Consistent with this finding, we have reported that NPC1 mouse models from different genetic backgrounds (BALB/cJ and C57BL/6J) that share similar decreased NPC1 gene dosage and loss-of-function mutations are predisposed to either weight gain in the absence of impaired glucose tolerance or impaired glucose tolerance in the absence of weight gain [24,25] . Therefore, the NPC1 polymorphisms at select loci are believed to adversely affect NPC1 protein function and predispose to either weight gain or impaired glucose tolerance depending on race/ethnicity, especially when combined with an obesogenic or diabetogenic environment [26] .…”

Role of thymol on hyperglycemia and hyperlipidemia in high fat diet-induced type 2 diabetic C57BL/6J mice

“…LDs consist of abundant neutral lipids such as TG, cholesterol esters and phospholipids. The increased hepatic glucose production and impaired glucose tolerance is associated with accumulation of liver FFAs and leads to hepatic lipotoxicity (Jelinek et al, 2013). In the hepatocytes increased retention of lipids in the form of TC, TG, PL and FFA results in fatty liver (Te Sligte et al, 2004).…”

Lipotoxicity in the Pancreatic Beta Cell: Not Just Survival and Function, but Proliferation as Well?

“…The cholesterol transport protein ABCG1 was increased in insulinoma tissue, and correlated with insulin secretion [55]. The intracellular cholesterol transport protein Npc1, genetically associated with risk of obesity in humans, may also play a role in insulin secretion [56]. LXR alpha, a receptor for cholesterol-related compounds, is important for insulin secretion in vitro and in vivo by altering glucose metabolism, ATP production and calcium channel flux; modulating its activity deregulated lipid metabolism via SREBP [57].…”