High-fat diet accelerates extreme obesity with hyperphagia in female heterozygous Mecp2-null mice
High-fat diet accelerates extreme obesity with hyperphagia in female heterozygous Mecp2-null mice
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DOI：
10.1371/journal.pone.0210184
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发表时间：
2019-01-04
期刊：
影响因子：
3.7
通讯作者：
Hosoi, Hajime
中科院分区：
文献类型：
--
作者：
Fukuhara, Shota;Nakajima, Hisakazu;Hosoi, Hajime
Rett综合征（RTT）是由甲基CpG结合蛋白2（MECP 2）基因突变引起的X连锁神经发育障碍。虽然RTT与肥胖有关，但其潜在机制尚未阐明。在这项研究中，雌性杂合Mecp 2-null小鼠（Mecp（2+/-）小鼠），RTT的模型，喂养正常的食物饮食或高脂饮食（HFD），并研究分子信号通路的变化。具体来说，我们研究了与下丘脑和多巴胺奖赏回路相关的基因的表达，这些基因代表了摄食行为控制的中枢网络。特别是，多巴胺奖赏回路已被证明可以调节享乐性进食行为，其破坏与HFD相关的可口性变化有关。喂食正常食物的Mecp（2+/-）小鼠表现出正常的体重和食物消耗，而喂食HFD的小鼠与喂食HFD的野生型小鼠（WT-HFD小鼠）相比表现出极度肥胖伴食欲过盛、体脂肪量增加、葡萄糖耐受不良和胰岛素抵抗。Mecp（2+/-）-HFD小鼠肥胖的主要原因是热量摄入的显著增加，而耗氧量或运动活性没有差异。在Mecp（2+/-）-HFD高瘦素血症小鼠中，Agouti相关肽mRNA和蛋白水平升高，而阿黑皮素原mRNA和蛋白水平降低，其在下丘脑的食欲和饱腹感中起重要作用。条件性位置偏爱实验显示Mecp（2+/-）小鼠偏爱HFD。与WT-HFD小鼠相比，Mecp（2+/-）-HFD小鼠腹侧被盖区的酪氨酸羟化酶和多巴胺转运蛋白mRNA水平以及中脑核中多巴胺受体和多巴胺-和cAMP-调节的磷蛋白mRNA水平显著降低。因此，在Mecp（2+/-）小鼠中，HFD喂养诱导下丘脑和多巴胺奖赏回路中食物摄入的失调，并加速与成瘾样进食行为相关的极度肥胖的发展。
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutation of the methyl-CpG-binding protein 2 (MECP2) gene. Although RTT has been associated with obesity, the underlying mechanism has not yet been elucidated. In this study, female heterozygous Mecp2-null mice (Mecp(2+/-) mice), a model of RTT, were fed a normal chow diet or high-fat diet (HFD), and the changes in molecular signaling pathways were investigated. Specifically, we examined the expression of genes related to the hypothalamus and dopamine reward circuitry, which represent a central network of feeding behavior control. In particular, dopamine reward circuitry has been shown to regulate hedonic feeding behavior, and its disruption is associated with HFD-related changes in palatability. The Mecp(2+/-) mice that were fed the normal chow showed normal body weight and food consumption, whereas those fed the HFD showed extreme obesity with hyperphagia, an increase of body fat mass, glucose intolerance, and insulin resistance compared with wild-type mice fed the HFD (WT-HFD mice). The main cause of obesity in Mecp(2+/-)-HFD mice was a remarkable increase in calorie intake, with no difference in oxygen consumption or locomotor activity. Agouti-related peptide mRNA and protein levels were increased, whereas proopiomelanocortin mRNA and protein levels were reduced in Mecp(2+/-)-HFD mice with hyperleptinemia, which play an essential role in appetite and satiety in the hypothalamus. The conditioned place preference test revealed that Mecp(2+/-) mice preferred the HFD. Tyrosine hydroxylase and dopamine transporter mRNA levels in the ventral tegmental area, and dopamine receptor and dopamine- and cAMP-regulated phosphoprotein mRNA levels in the nucleus accumbens were significantly lower in Mecp(2+/-)-HFD mice than those of WT-HFD mice. Thus, HFD feeding induced dysregulation of food intake in the hypothalamus and dopamine reward circuitry, and accelerated the development of extreme obesity associated with addiction-like eating behavior in Mecp(2+/-) mice.