title: Haploinsufficiency in the PPARalpha and LDL receptor genes leads to gender- and age-specific obesity and hyperinsulinemia.
abstract: When preparing peroxisome proliferator-activated receptor (PPAR)alpha:low-density lipoprotein receptor (LDLR) (-/-) double knockout mice, we unexpectedly found a unique gender- and age-specific obesity in the F1 generation, PPARalpha (+/-):LDLR (+/-), even in mice fed standard chow. Body weights of the male heterozygous mice increased up to about 60 g at 75 weeks of age, then decreased by about 30 g at 100 weeks of age. More than 95% of the heterozygous mice between 35- and 75-week-olds were overweight. Of interest, the obese heterozygous mice also exhibited hyperinsulinemia correlating with moderate insulin resistance. Hepatic gene expression of LDLR was lower than expected in the heterozygous mice, particularly at 50 and 75 weeks of age. In contrast, the hepatic expression of PPARalpha was higher than expected in obese heterozygous mice, but decreased in non-obese older heterozygous mice. Modulated expression of these genes may be partially associated with the onset of the hyperinsulinemia.
authors.affiliation: The Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, Nagano 390-8621, Japan. eikoyoko@nagano-kentan.ac.jp
authors.forename: Eiko
authors.initials: E
authors.lastname: Sugiyama
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Tamie
authors.initials: T
authors.lastname: Nakajima
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kamijo
authors.forename: Shin
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Li
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Aoyama
mesh_terms: D000367:Age Factors; D000818:Animals; D005260:Female; D005951:Glucose Tolerance Test; D006579:Heterozygote; D006946:Hyperinsulinism / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D012737:Sex Factors
chemical_list: D007328:Insulin; D008055:Lipids; D047493:PPAR alpha; D012333:RNA, Messenger; D011973:Receptors, LDL