Visceral Fat Accumulation in NDN KO Mice is Associated with Increased Fatty Acid Uptake

Abstract

Prader-Willi syndrome (PWS) is a genetic disease characterized by the loss of paternal expression of all the genes at 15q11-q13, including the NDN gene. NDN-KO mice are among the model mice whose PWS phenotype is partially correlated with one another. Because abnormalities in fat tissues appear before the start of hyperphagia-induced weight gain, we examined fat tissues from NDN-KO mice. Along with increased leptin mRNA expression, the epididymal fat weight/body weight ratio was significantly greater in NDN-/- KO-type mice after 10 weeks of feeding a normal diet. However, body weight and food intake were not altered between NDN+/+ wild-type and NDN-/- KO-type mice. We examined adipocyte-related gene expression and found that adipoQ expression was significantly decreased by 40% in NDN-/- KO-type mice. Because a reduction in the adipoQ level is correlated with insulin resistance, we assessed insulin-induced glucose uptake. 2-DG uptake was lower in epididymal fat cells from NDN-/- KO-type mice than in those from NDN+/+ wild-type mice under both basal and insulin-stimulated conditions. Fat accumulation in adipose tissues is regulated by lipolysis and lipogenesis. The expression of genes related to lipolysis, including ATGL, HSL, and perilipin, was not altered, and the isoprenaline-stimulated release of glycerol through the lipolysis process was the same in NDN-/- KO-type mice as in NDN+/+ wild-type mice. We next examined the expression of genes related to lipogenesis, including FATP1, FATP4, DGAT1, and FAS. Among them, FATP4 and FAS expression levels were significantly increased by 1.5-fold in NDN-/- KO-type mice. Additionally, fat cells from NDN-/- KO-type mice exhibited a 5-fold greater amount of fatty acid incorporation than those from NDN+/+ wild-type mice. Furthermore, we observed profound epididymal fat accumulation after an additional 10 days of high-fat diet feeding. Our findings may at least partly reflect the underlying pathology of adipose tissues in PWS.

Note:
Funding Information: This work was supported by a grant from the Takeda Science Foundation.

Conflict of Interests: We have no conflict of interest or competing interest.

Ethical Approval: Experiments using gene-targeted mice were approved by the Animal Experiment Committees of Ritsumeikan University (BKC-2021-034) and were performed in accordance with institutional guidelines and regulations

Keywords: The NDN gene, Prader-Willi syndrome, Fat accumulation, lipolysis, Lipogenesis, Fatty acid uptake