Hypomorphism of Fto and Rpgrip1l causes obesity in mice

Noncoding polymorphisms in the fat mass and obesity-associated (FTO) gene represent common alleles that are strongly associated with effects on food intake and adiposity in humans. Previous studies have suggested that the obesity-risk allele rs8050136 in the first intron of FTO alters a regulatory e...

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Published in:	The Journal of clinical investigation 2016-05, Vol.126 (5), p.1897-1910
Main Authors:	Stratigopoulos, George, Burnett, Lisa Cole, Rausch, Richard, Gill, Richard, Penn, David Barth, Skowronski, Alicja A, LeDuc, Charles A, Lanzano, Anthony J, Zhang, Pumin, Storm, Daniel R, Egli, Dieter, Leibel, Rudolph L
Format:	Article
Language:	eng
Subjects:	African Americans Alleles Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics Alpha-Ketoglutarate-Dependent Dioxygenase FTO - metabolism Analysis Animals Energy Metabolism - genetics Experiments Food Gene Expression Regulation Genetic aspects Haplotypes Homeodomain Proteins - biosynthesis Homeodomain Proteins - genetics Homeostasis Humans Hypothalamus - metabolism Hypothalamus - pathology Introns Mice Mice, Transgenic Obesity Obesity - genetics Obesity - metabolism Obesity - pathology Polymorphism, Single Nucleotide Proteins Proteins - genetics Proteins - metabolism Retinoblastoma-Like Protein p130 - biosynthesis Retinoblastoma-Like Protein p130 - genetics Risk factors Rodents Single nucleotide polymorphisms Studies Transcription Factors - biosynthesis Transcription Factors - genetics
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Summary:	Noncoding polymorphisms in the fat mass and obesity-associated (FTO) gene represent common alleles that are strongly associated with effects on food intake and adiposity in humans. Previous studies have suggested that the obesity-risk allele rs8050136 in the first intron of FTO alters a regulatory element recognized by the transcription factor CUX1, thereby leading to decreased expression of FTO and retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L). Here, we evaluated the effects of rs8050136 and another potential CUX1 element in rs1421085 on expression of nearby genes in human induced pluripotent stem cell-derived (iPSC-derived) neurons. There were allele-dosage effects on FTO, RPGRIP1L, and AKT-interacting protein (AKTIP) expression, but expression of other vicinal genes, including IRX3, IRX5, and RBL2, which have been implicated in mediating functional effects, was not altered. In vivo manipulation of CUX1, Fto, and/or Rpgrip1l expression in mice affected adiposity in a manner that was consistent with CUX1 influence on adiposity via remote effects on Fto and Rpgrip1l expression. In support of a mechanism, mice hypomorphic for Rpgrip1l exhibited hyperphagic obesity, as the result of diminished leptin sensitivity in Leprb-expressing neurons. Together, the results of this study indicate that the effects of FTO-associated SNPs on energy homeostasis are due in part to the effects of these genetic variations on hypothalamic FTO, RPGRIP1L, and possibly other genes.
ISSN:	0021-9738 1558-8238