Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome

被引:83
作者
Burns, Brooke [2 ]
Schmidt, Kristie [2 ]
Williams, Stephen R. [2 ]
Kim, Sun [2 ]
Girirajan, Santhosh [2 ]
Elsea, Sarah H. [1 ,2 ]
机构
[1] Virginia Commonwealth Univ, Dept Pediat, Richmond, VA 23298 USA
[2] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA 23298 USA
关键词
SMITH-MAGENIS-SYNDROME; NEUROTROPHIC FACTOR BDNF; OBSESSIVE-COMPULSIVE DISORDER; ADIPOSE-SPECIFIC PROTEIN; NEUROPEPTIDE-Y; MOUSE MODELS; LEPTIN RESISTANCE; CIRCADIAN-RHYTHM; FOOD-INTAKE; SUPPRESSES GHRELIN;
D O I
10.1093/hmg/ddq317
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
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.
引用
收藏
页码:4026 / 4042
页数:17
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