Decreased Npc1 gene dosage in mice is associated with weight gain.
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.
Jelinek
David
D
Department of Pediatrics, The University of Arizona, Tucson, Arizona, USA.
Heidenreich
Randall A
RA
Erickson
Robert P
RP
Garver
William S
WS
D000273:Adipose Tissue / Q000473:pathology; D000821:Animal Feed; D000818:Animals; D001835:Body Weight / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology; D005260:Female; D018628:Gene Dosage / Q000502:physiology*; D006579:Heterozygote; D006720:Homozygote; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D000077296:Niemann-Pick C1 Protein; D009767:Obesity, Morbid / Q000235:genetics* / Q000473:pathology*; D009929:Organ Size; D011506:Proteins / Q000235:genetics*; D015430:Weight Gain / Q000235:genetics*
D004041:Dietary Fats; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins