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首页> 外文期刊>Human Molecular Genetics >Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome.
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Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome.

机译：Rai1单倍剂量不足会导致Bdnf表达降低，从而导致小鼠和人类中的食欲亢进，肥胖和脂肪分布改变，而没有代谢综合征的迹象。

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摘要

Smith-Magenis syndrome (SMS) is a genetic disorder caused by haploinsufficiency of the retinoic acid induced 1 (RAI1) gene. In addition to intellectual disabilities, behavioral abnormalities and sleep disturbances, a majority of children with SMS also have significant early-onset obesity. To study the role of RAI1 in obesity, we investigated the growth and obesity phenotype in a mouse model haploinsufficient for Rai1. Data show that Rai1(+/-) mice are hyperphagic, have an impaired satiety response and have altered abdominal and subcutaneous fat distribution, with Rai1(+/-) female mice having a higher proportion of abdominal fat when compared with wild-type female mice. Expression analyses revealed that Bdnf (brain-derived neurotrophic factor), a gene previously associated with hyperphagia and obesity, is downregulated in the Rai1(+/-) mouse hypothalamus, and reporter studies show that RAI1 directly regulates the expression of BDNF. Even though the Rai1(+/-) mice are significantly obese, serum analyses do not reveal any evidence of metabolic syndrome. Supporting these findings, a caregiver survey revealed that even though a high incidence of abdominal obesity is observed in females with SMS, they did not exhibit a higher incidence of indicators of metabolic syndrome above the general population. We conclude that Rai1 haploinsufficiency represents a single-gene model of obesity with hyperphagia, abnormal fat distribution and altered hypothalamic gene expression associated with satiety, food intake, behavior and obesity. Linking RAI1 and BDNF provides a more thorough understanding of the role of Rai1 in growth and obesity and insight into the complex pathogenicity of obesity, behavior and sex-specific differences in adiposity.
机译：Smith-Magenis综合征（SMS）是由视黄酸诱导1（RAI1）基因的单倍缺乏引起的遗传性疾病。除智力障碍，行为异常和睡眠障碍外，大多数SMS患儿还患有严重的早期肥胖症。若要研究RAI1在肥胖中的作用，我们调查了Rai1单倍体不足的小鼠模型中的生长和肥胖表型。数据显示，Rai1（+/-）小鼠食欲亢进，饱腹感受损，腹部和皮下脂肪分布发生变化，与野生型雌性相比，Rai1（+/-）雌性小鼠的腹部脂肪比例更高老鼠。表达分析表明，Bdnf（脑源性神经营养因子）是一种以前与食欲亢进和肥胖有关的基因，在Rai1（+/-）小鼠下丘脑中被下调，而且记者研究表明RAI1直接调节BDNF的表达。即使Rai1（+/-）小鼠非常肥胖，血清分析也没有发现代谢综合征的任何证据。支持这些发现的一项护理人员调查显示，即使在患有SMS的女性中观察到腹部肥胖的发生率很高，但与一般人群相比，他们没有表现出较高的代谢综合征指标发生率。我们得出的结论是，Rai1单倍剂量不足代表肥胖的单基因模型，具有食欲亢进，脂肪分布异常和下丘脑基因表达改变（与饱腹感，食物摄入，行为和肥胖有关）。通过将RAI1和BDNF链接起来，可以更全面地了解Rai1在生长和肥胖中的作用，并深入了解肥胖，行为和肥胖中性别特异性差异的复杂致病性。

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