title: Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome.
abstract: 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.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Brooke
authors.initials: B
authors.lastname: Burns
authors.forename: Kristie
authors.initials: K
authors.lastname: Schmidt
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Williams
authors.forename: Sun
authors.initials: S
authors.lastname: Kim
authors.forename: Santhosh
authors.initials: S
authors.lastname: Girirajan
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Elsea
mesh_terms: D000818:Animals; D050218:Body Fat Distribution; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D057895:Haploinsufficiency; D006801:Humans; D006963:Hyperphagia / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009765:Obesity / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012528:Satiety Response; D058496:Smith-Magenis Syndrome / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C431552:RAI1 protein, human; C502844:Rai1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors