Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome
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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DOI：
10.1093/hmg/ddq317
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发表时间：
2010-10-15
影响因子：
3.5
通讯作者：
Elsea, Sarah H.
中科院分区：
文献类型：
--
作者：
Burns, Brooke;Schmidt, Kristie;Elsea, Sarah H.
Smith-Magenis综合征（SMS）是由视黄酸诱导1（RAI 1）基因的单倍不足引起的遗传性疾病。除了智力障碍、行为异常和睡眠障碍外，大多数SMS儿童还具有明显的早发性肥胖。为了研究RAI 1在肥胖中的作用，我们研究了Rai 1单倍体不足的小鼠模型的生长和肥胖表型。数据显示，Rai 1（+/-）小鼠贪食，饱腹感反应受损，腹部和皮下脂肪分布改变，与野生型雌性小鼠相比，Rai 1（+/-）雌性小鼠的腹部脂肪比例更高。表达分析显示，BDNF（脑源性神经营养因子），一个基因先前与暴食症和肥胖症，下调在Rai 1（+/-）小鼠下丘脑，和报告研究表明，RAI 1直接调节BDNF的表达。尽管Rai 1（+/-）小鼠明显肥胖，但血清分析未显示任何代谢综合征的证据。支持这些研究结果，护理人员调查显示，即使在SMS女性中观察到腹部肥胖的高发病率，但他们并没有表现出高于一般人群的代谢综合征指标的发病率。我们的结论是，Rai 1单倍不足代表了一个单基因模型的肥胖与暴食，脂肪分布异常和改变下丘脑基因表达与饱腹感，食物摄入量，行为和肥胖。将RAI 1和BDNF联系起来，可以更深入地了解RAI 1在生长和肥胖中的作用，并深入了解肥胖的复杂致病性，肥胖的行为和性别特异性差异。
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.