Involvement of apolipoprotein E in excess fat accumulation and insulin resistance.
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.
Gao
Junhong
J
Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Katagiri
Hideki
H
Ishigaki
Yasushi
Y
Yamada
Tetsuya
T
Ogihara
Takehide
T
Imai
Junta
J
Uno
Kenji
K
Hasegawa
Yutaka
Y
Kanzaki
Makoto
M
Yamamoto
Tokuo T
TT
Ishibashi
Shun
S
Oka
Yoshitomo
Y
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
D001057:Apolipoproteins E; D014280:Triglycerides; D019000:Phosphotyrosine; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase