Journal Article

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

Brooke Burns, Kristie Schmidt, Stephen R. Williams, Sun Kim, Santhosh Girirajan and Sarah H. Elsea

in Human Molecular Genetics

Volume 19, issue 20, pages 4026-4042
Published in print October 2010 | ISSN: 0964-6906
Published online July 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq317
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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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.

Journal Article.  9741 words.  Illustrated.

Subjects: Genetics and Genomics

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