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: Brooke Burns, Kristie Schmidt, Stephen R Williams, Sun Kim, Santhosh Girirajan, Sarah H Elsea
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 19 Issue 20 Pg. 4026-42 (Oct 15 2010) ISSN: 1460-2083 [Electronic] England
• PMID: 20663924 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Brain-Derived Neurotrophic Factor
• RAI1 protein, human
• Rai1 protein, mouse
• Trans-Activators
• Transcription Factors

Topics

• Animals
• Body Fat Distribution
• Brain-Derived Neurotrophic Factor (genetics, metabolism)
• Disease Models, Animal
• Female
• Gene Expression
• HEK293 Cells
• Haploinsufficiency
• Humans
• Hyperphagia (genetics)
• Mice
• Mice, Knockout
• Microarray Analysis
• Obesity (genetics)
• Polymerase Chain Reaction
• Satiety Response
• Smith-Magenis Syndrome (genetics, metabolism)
• Trans-Activators (genetics)
• Transcription Factors (genetics)