title: Involvement of apolipoprotein E in excess fat accumulation and insulin resistance.
abstract: Although apolipoprotein E (apoE) is well known to play a major role in lipid metabolism, its role in glucose and energy homeostasis remains unclear. Herein, we established apoE-deficient genetically obese Ay (apoE(-/-);Ay/+) mice. ApoE deficiency in Ay mice prevented the development of obesity, with decreased fat accumulation in the liver and adipose tissues. ApoE(-/-);Ay/+ mice exhibited better glucose tolerance than apoE(+/+);Ay/+ mice. Insulin tolerance testing and hyperinsulinemic-euglycemic clamp study revealed marked improvement of insulin sensitivity, despite increased plasma free fatty acid levels. These metabolic phenotypes were reversed by adenoviral replenishment of apoE protein, indicating circulating apoE to be involved in increased adiposity and obesity-related metabolic disorders. Uptake of apoE-lacking VLDL into the liver and adipocytes was markedly inhibited, but adipocytes in apoE(-/-);Ay/+ mice exhibited normal differentiation, suggesting that apoE-dependent VLDL transport is involved in the development of obesity, i.e., surplus fat accumulation. Interestingly, apoE(-/-);Ay/+ mice exhibited decreased food intake and increased energy expenditure. Pair-feeding experiments indicate these phenomena to both contribute to the obesity-resistant phenotypes associated with apoE deficiency. Thus, apoE is involved in maintaining energy homeostasis. ApoE-dependent excess fat accumulation is a promising therapeutic target for the metabolic syndrome.
authors.affiliation: Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Junhong
authors.initials: J
authors.lastname: Gao
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishigaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamada
authors.forename: Takehide
authors.initials: T
authors.lastname: Ogihara
authors.forename: Junta
authors.initials: J
authors.lastname: Imai
authors.forename: Kenji
authors.initials: K
authors.lastname: Uno
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Kanzaki
authors.forename: Tokuo T
authors.initials: TT
authors.lastname: Yamamoto
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
mesh_terms: D000273:Adipose Tissue / Q000033:anatomy & histology* / Q000502:physiology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D001835:Body Weight; D010122:Cystinyl Aminopeptidase / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D019000:Phosphotyrosine / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D014280:Triglycerides; D019000:Phosphotyrosine; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase