The C57BL/6J Niemann-Pick C1 mouse model with decreased gene dosage is susceptible to increased weight gain when fed a high-fat diet: Confirmation of a gene-diet interaction

Jelínek, David; Castillo, Joseph; Heidenreich, Randall A.; Garver, William S.

doi:10.1016/j.gene.2015.05.025

Cited by 8 publications

(6 citation statements)

References 18 publications

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“…Similar sex-specific associations were found in NPC1 heterozygous knock-out ( NPC1 +/ − ) mice fed a high fat diet (HFD) with significant differences in body weight observed as the mice reached maturity 14 . Other studies also observed a latent weight gain in NPC1 +/ − mice fed a HFD 22 – 25 , supporting the adult onset of obesity observed in human NPC1 variant carriers 13 , 21 . More recently, studies have reported that NPC1 +/− mice fed a high-fat diet are physiologically characterized with increased liver glycolysis and lipogenesis, and decreased adipose lipolysis through impaired feedback inhibition of the sterol regulatory element binding protein-1 (SREBP-1) pathway.…”

Section: Introductionsupporting

confidence: 52%

Signatures of natural selection and ethnic-specific prevalence of NPC1 pathogenic mutations contributing to obesity and Niemann–Pick disease type C1

Chiorean

Garver

Meyre

2020

Sci Rep

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While homozygous pathogenic mutations in the NPC1 gene cause Niemann-Pick type C1 disease, heterozygous mutations cause highly-penetrant obesity. We aimed to investigate the prevalence of NPC1 mutations and their signatures of natural selection in 122,678 exome sequenced participants from six ethnic groups in the Genome Aggregation Database. Pathogenic missense coding mutations were identified by in silico tools and the ClinVar database. Signatures of natural selection were assessed by the probability of NPC1 being loss-of-function mutation intolerant and Z-scores of observed/expected synonymous and non-synonymous mutation ratios. There was no evidence of negative selection observed for synonymous, non-synonymous and loss-of-function mutations. However, there were significant ethnic differences in the prevalence of heterozygous pathogenic NPC1 mutations ranging from 0.56% in Ashkenazi Jewish to 3.26% in African/African Americans (5.8-fold difference). Four homozygous carriers of pathogenic NPC1 mutations were also identified, belonging to the South Asian population. In conclusion, NPC1 mutations are consistent with a model of balanced selection, where heterozygotes and homozygotes have higher and lower reproductive fitness, respectively. Therefore, NPC1 heterozygous mutations may account for a substantial and ethnic-dependent percentage of obesity in the general population, while NPC1 homozygous mutations may be frequent in the South Asian populations and warrants more investigation.

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Section: Introductionsupporting

confidence: 52%

Signatures of natural selection and ethnic-specific prevalence of NPC1 pathogenic mutations contributing to obesity and Niemann–Pick disease type C1

Chiorean

Garver

Meyre

2020

Sci Rep

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“…--SRT (Platt et al, 1997) (Sango et al, 1995) + + AAV (Sargeant et al, 2011;Cachon-Gonzalez et al, 2014), BMT (Norflus et al, 1998;Wada et al, 2000), CM (Pelled et al, 2003), Diet (Denny et al, 2010), HSP (Kirkegaard et al, 2016), MIP-1 (Wu and Proia, 2004), SRT (Jeyakumar et al, 1999) HexB ( Npc1 (−/−) (Morris et al, 1977) + -AAV (Chandler et al, 2017b;Xie et al, 2017;Hughes et al, 2018), AI (Alvarez et al, 2008), AO (Fu et al, 2013), CM (Erickson et al, 2000;Repa et al, 2007;Abi-Mosleh et al, 2009;Liu et al, 2010;Taylor et al, 2012;Hovakimyan et al, 2013;Nusca et al, 2014;Tanaka et al, 2014;Soga et al, 2015;Demais et al, 2016), Diet (Jelinek et al, 2015;Soga et al, 2015), HSP (Chung et al, 2016;Kirkegaard et al, 2016), NS (Griffin et al, 2004;Liao et al, 2009), Transplant (Veyron et al, 1996) Npc1 (Otterbach and Stoffel, 1995) + +…”

Section: Metachromatic Leukodystrophymentioning

confidence: 99%

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

Favret

Weinstock

Feltri

et al. 2020

Front. Mol. Biosci.

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There are over 50 lysosomal hydrolase deficiencies, many of which cause neurodegeneration, cognitive decline and death. In recent years, a number of broad innovative therapies have been proposed and investigated for lysosomal storage diseases (LSDs), such as enzyme replacement, substrate reduction, pharmacologic chaperones, stem cell transplantation, and various forms of gene therapy. Murine models that accurately reflect the phenotypes observed in human LSDs are critical for the development, assessment and implementation of novel translational therapies. The goal of this review is to summarize the neurodegenerative murine LSD models available that recapitulate human disease, and the pre-clinical studies previously conducted. We also describe some limitations and difficulties in working with mouse models of neurodegenerative LSDs.

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“…This study was extended using BALB/cJ-C57BL/6J hybrid Npc1 +/- mice that were also susceptible to weight gain and impaired glucose tolerance when fed a high-fat diet compared to hybrid Npc1 +/+ mice fed the same diet [ 105 ]. Moreover, a subsequent study found that the C57BL/6J Npc1 +/- mice are susceptible to weight gain when fed a high-fat diet compared to C57BL/6J Npc1 +/+ mice fed the same diet [ 106 ]. An independent study has since been reported that rare human NPC1 gene loss-of-function mutations among male heterozygotes (but not female heterozygotes) have a significantly higher BMI compared to matched controls and that Npc1 +/- mice fed a HFD have significantly increased fat storage compared to Npc1 +/+ mice fed the same diet [ 107 ].…”

Section: Gene-nutrient Interactions That Promote Obesitymentioning

confidence: 99%

Gene-nutrient interactions and susceptibility to human obesity

2017

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A large number of genome-wide association studies, transferability studies, and candidate gene studies performed in diverse populations around the world have identified gene variants that are associated with common human obesity. The mounting evidence suggests that these obesity gene variants interact with multiple environmental factors and increase susceptibility to this complex metabolic disease. The objective of this review article is to provide concise and updated information on energy balance, heritability of body weight, origins of gene variants, and gene-nutrient interactions in relation to human obesity. It is proposed that knowledge of these related topics will provide valuable insight for future preventative lifestyle intervention using targeted nutritional and medicinal therapies.

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The C57BL/6J Niemann-Pick C1 mouse model with decreased gene dosage is susceptible to increased weight gain when fed a high-fat diet: Confirmation of a gene-diet interaction

Cited by 8 publications

References 18 publications

Signatures of natural selection and ethnic-specific prevalence of NPC1 pathogenic mutations contributing to obesity and Niemann–Pick disease type C1

Signatures of natural selection and ethnic-specific prevalence of NPC1 pathogenic mutations contributing to obesity and Niemann–Pick disease type C1

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

Gene-nutrient interactions and susceptibility to human obesity

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