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Decreased Npc1 gene dosage in mice is associated with weight gain.

ABSTRACT: A recent genome-wide association study has determined that the Niemann-Pick C1 (NPC1) gene is associated with early-onset and morbid adult obesity. However, what effects of the nonsynonymous variation in NPC1 on protein function result in weight gain remains unknown. The NPC1 heterozygous mouse model (Npc1(+/-)), which expresses one-half the normal amounts of functional Npc1 protein compared to the homozygous normal (Npc1(+/+)) mouse, was used to determine whether decreased Npc1 gene dosage was associated with weight gain when fed either a low-fat (10% kcal fat) or high-fat (45% kcal fat) diet beginning at 4 weeks of age until 20 weeks of age. The results indicated that Npc1(+/-) mice had significantly increased weight gain beginning at 13 weeks of age when fed a high-fat diet, but not when fed a low-fat diet, compared to the Npc1(+/+) mice fed the same diet. With respect to mice fed a high-fat diet, the Npc1(+/-) mice continued to have significantly increased weight gain to 30 weeks of age. At this age, the Npc1(+/-) mice were found to have increased liver and inguinal adipose weights compared to the Npc1(+/+) mice. Therefore, decreased Npc1 gene dosage resulting in decreased Npc1 protein function, promoted weight gain in mice fed a high-fat diet consistent with a gene-diet interaction.

SUBMITTER: Jelinek D

PROVIDER: S-EPMC3101636 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Decreased Npc1 gene dosage in mice is associated with weight gain.

Jelinek David D Heidenreich Randall A RA Erickson Robert P RP Garver William S WS

Obesity (Silver Spring, Md.) 20091112 7

A recent genome-wide association study has determined that the Niemann-Pick C1 (NPC1) gene is associated with early-onset and morbid adult obesity. However, what effects of the nonsynonymous variation in NPC1 on protein function result in weight gain remains unknown. The NPC1 heterozygous mouse model (Npc1(+/-)), which expresses one-half the normal amounts of functional Npc1 protein compared to the homozygous normal (Npc1(+/+)) mouse, was used to determine whether decreased Npc1 gene dosage was ...[more]

PMID: 19910939

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Project description:Robustness to perturbation, or canalization, is a fundamental and required feature of complex organisms.1 Mutations are the raw material for evolution, but robustness to their effects is required for organisms to tolerate mutational loads.1 Similarly, robustness to environmental perturbations, or limiting environmental responses to an adaptive range, is necessary for organisms to tolerate environmental variation. Robustness is heritable2-4, but the mechanisms that produce it are poorly understood. Explanations range from the role of specific processes such as heat shock proteins to more general embedded features of developmental systems. Nonlinearities are an embedded, ubiquitous feature of development that may modulate how variation in development relates to phenotypic robustness.5,6 Here, we show that variation in Fibroblast Growth Factor 8 (Fgf8) expression across an allelic series has a nonlinear relationship to phenotypic variation, predicting the magnitude of variation within genotypes. These differences in phenotypic variance are independent of genetic variance and so reflect differential robustness to minor environmental variation. Differences in robustness are not related to differences in the variance of gene expression within genotypes. However, mean gene expression levels do vary across genotypes, particularly in genes downstream to FGF8 signaling. Gene expression changes thus explain the genotype-phenotype curve but not the changes in robustness along the curve. This suggests that mechanisms above the gene-regulatory network are important determinants of robustness. Our results show that nonlinearities in developmental mechanisms can persist from genotype to phenotype to produce variation in robustness between genotypes. This suggests that embedded features of development rather than specific canalizing mechanisms explain robustness. How such features vary among individuals in natural populations and relate to genetic variation more generally are key questions for unravelling the origin and evolvability of this fundamental feature of organismal development.

Dataset Information

Decreased Npc1 gene dosage in mice is associated with weight gain.

Publications

Decreased Npc1 gene dosage in mice is associated with weight gain.

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