Wakana Noriyuki, Irie Daisuke, Kikai Masakazu, Terada Kensuke, Yamamoto Keita, Kawahito Hiroyuki, Kato Taku, Ogata Takehiro, Ueyama Tomomi, Matoba Satoaki, Yamada Hiroyuki
From the Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Arterioscler Thromb Vasc Biol. 2015 Mar;35(3):558-69. doi: 10.1161/ATVBAHA.114.305122. Epub 2015 Jan 15.
Maternal obesity elicits offspring's metabolic disorders via developmental modifications of visceral adipose tissue; however, its effect on atherogenesis remains undefined. Perivascular adipose tissue has recently been implicated in vascular remodeling and vasoreactivity. We hypothesize that developmental modifications of perivascular adipose tissue by maternal high-fat diet (HFD) exposure promotes atherosclerosis in adult offspring.
Eight-week-old female apolipoprotein E-deficient mice were fed an HFD or normal diet (ND) during gestation and lactation. Offspring were fed a high-cholesterol diet from 8 weeks of age. Twenty-week-old male offspring of HFD-fed dams (O-HFD) showed a 2.1-fold increase in atherosclerotic lesion of the entire aorta compared with those of ND-fed dams (O-ND). Although mRNA expressions of interleukin-6, tumor necrosis factor, and monocyte chemotactic protein-1 and accumulation of macrophages in epididymal white adipose tissue were less in O-HFD than in O-ND, thoracic periaortic adipose tissue (tPAT) showed an exaggerated inflammatory response in O-HFD. Intra-abdominal transplantation of tPAT from 8-week-old O-HFD alongside the distal abdominal aorta exaggerated atherosclerosis development of the infrarenal aorta in recipient apolipoprotein E-deficient mice compared with tPAT from O-ND (210%, P<0.01). Although macrophage accumulation was rarely detected in tPAT of 8-week-old offspring, mRNA expression and protein levels of macrophage colony-stimulating factor were markedly elevated in O-HFD (2.3-fold, 3.3-fold, respectively, P<0.05), suggesting that increased macrophage colony-stimulating factor expression contributes to the augmented accumulation of macrophages, followed by the enhanced proinflammatory response.
Our findings demonstrate that maternal HFD exaggerates atherosclerosis development in offspring by augmenting tPAT-specific inflammatory response proceeded by an increased expression of macrophage colony-stimulating factor.
母体肥胖通过内脏脂肪组织的发育改变引发子代的代谢紊乱；然而，其对动脉粥样硬化形成的影响仍不明确。血管周围脂肪组织最近被认为与血管重塑和血管反应性有关。我们假设，母体高脂饮食（HFD）暴露引起的血管周围脂肪组织发育改变会促进成年子代的动脉粥样硬化。
8周龄的载脂蛋白E缺陷雌性小鼠在妊娠和哺乳期喂食高脂饮食或正常饮食（ND）。子代从8周龄开始喂食高胆固醇饮食。与喂食正常饮食母鼠的子代（O-ND）相比，喂食高脂饮食母鼠的20周龄雄性子代（O-HFD）整个主动脉的动脉粥样硬化病变增加了2.1倍。尽管O-HFD组附睾白色脂肪组织中白细胞介素-6、肿瘤坏死因子和单核细胞趋化蛋白-1的mRNA表达以及巨噬细胞的积聚均低于O-ND组，但O-HFD组胸主动脉周围脂肪组织（tPAT）表现出过度的炎症反应。与移植O-ND组的tPAT相比，将8周龄O-HFD组的tPAT移植到受体载脂蛋白E缺陷小鼠腹主动脉远端旁，会加剧肾下腹主动脉的动脉粥样硬化发展（210%，P<0.01）。尽管在8周龄子代的tPAT中很少检测到巨噬细胞积聚，但O-HFD组中巨噬细胞集落刺激因子的mRNA表达和蛋白水平显著升高（分别为2.3倍和3.3倍，P<0.05），这表明巨噬细胞集落刺激因子表达增加有助于巨噬细胞积聚增加，进而增强促炎反应。
我们的研究结果表明，母体高脂饮食通过增强tPAT特异性炎症反应（由巨噬细胞集落刺激因子表达增加所致），加剧子代的动脉粥样硬化发展。
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