Leptin receptor-deficient (knockout) medaka, Oryzias latipes, show chronical up-regulated levels of orexigenic neuropeptides, elevated food intake and stage specific effects on growth and fat allocation
Leptin receptor-deficient (knockout) medaka, Oryzias latipes, show chronical up-regulated levels of orexigenic neuropeptides, elevated food intake and stage specific effects on growth and fat allocation
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DOI：
10.1016/j.ygcen.2013.10.008
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发表时间：
2014-01-01
影响因子：
2.7
通讯作者：
Yoshiura, Yasutoshi
中科院分区：
文献类型：
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作者：
Chisada, Shin-ichi;Kurokawa, Tadahide;Yoshiura, Yasutoshi
首次在哺乳动物身上发现瘦素及其受体（LepR）的研究，是基于在体重和能量平衡调节方面表现出巨大变化的突变动物。随后的研究表明，在恒温哺乳动物中，瘦素或LepR的缺乏会导致贪食、肥胖、不育和许多其他异常。瘦素介导的信号在异温硬鱼中的生理作用仍在探索中。在这里，我们利用基因组法靶向诱导局部病变，产生了纯合子LepR基因突变的medaka。该基因敲除突变体在瘦素结合域前的第357个氨基酸上有半胱氨酸终止密码子的点突变。在突变体中，瘦素介导的信号功能丧失的证据是基于间脑中关键的食欲相关神经肽的表达缺乏对摄食的反应。突变体lepr(-/-) medaka在间脑中表达了持续上调的厌氧性神经肽Ya和agoutii相关蛋白mRNA水平，以及独立于摄食的厌氧性proopiomelanocortin 1水平的抑制，这表明该突变体不具有功能性lepr。分析了lepr突变体medaka的表型，以了解其对食物摄入、生长和组织脂肪积累的影响。突变体medaka在幼鱼后期和成鱼阶段的摄取量高于野生型（WT）鱼。嗜食导致幼鱼后期的高生长速率，但对最终成鱼的体型没有显著改变。在少年后和成年突变体中，肝脏和肌肉中没有额外的脂肪沉积，在成年突变体中，血浆中也没有额外的脂肪沉积。然而，成年麻风病突变体拥有大量内脏脂肪沉积，这与没有内脏脂肪沉积的WT鱼不同。我们的分析证实了medaka的LepR对食物摄入的控制有强大的影响。使用突变体的进一步分析将有助于更好地理解瘦素在鱼类中的作用。这是首次对瘦素受体缺乏的鱼进行研究。(C) 2013爱思唯尔公司版权所有。
The first studies that identified leptin and its receptor (LepR) in mammals were based on mutant animals that displayed dramatic changes in body-weight and regulation of energy homeostasis. Subsequent studies have shown that a deficiency of leptin or LepR in homoeothermic mammals results in hyperphagia, obesity, infertility and a number of other abnormalities. The physiological roles of leptin-mediated signaling in ectothermic teleosts are still being explored. Here, we produced medaka with homozygous LepR gene mutation using the targeting induced local lesions in a genome method. This knockout mutant had a point mutation of cysteine for stop codon at the 357th amino acid just before the leptin-binding domain. The evidence for loss of function of leptin-mediated signaling in the mutant is based on a lack of response to feeding in the expression of key appetite-related neuropeptides in the diencephalon. The mutant lepr(-/-) medaka expressed constant up-regulated levels of mRNA for the orexigenic neuropeptide Ya and agoutirelated protein and a suppressed level of anorexigenic proopiomelanocortin 1 in the diencephalon independent of feeding, which suggests that the mutant did not possess functional LepR. Phenotypes of the LepR-mutant medaka were analyzed in order to understand the effects on food intake, growth, and fat accumulation in the tissues. The food intake of the mutant medaka was higher in post-juveniles and adult stages than that of wild-type (WT) fish. The hyperphagia led to a high growth rate at the post-juvenile stage, but did not to significant alterations in final adult body size. There was no additional deposition of fat in the liver and muscle in the post-juvenile and adult mutants, or in the blood plasma in the adult mutant. However, adult LepR mutants possessed large deposits of visceral fat, unlike in the WT fish, in which there were none. Our analysis confirms that LepR in medaka exert a powerful influence on the control on food intake. Further analyses using the mutant will contribute to a better understanding of the role of leptin in fish. This is the first study to produce fish with leptin receptor deficiency. (C) 2013 Elsevier Inc. All rights reserved.