RESUMO
Two recent, large whole-genome association studies (GWAS) in European populations have associated a approximately 47-kb region that contains part of the FTO gene with high body mass index (BMI). The functions of FTO and adjacent FTM in human biology are not clear. We examined expression of these genes in organs of mice segregating for monogenic obesity mutations, exposed to underfeeding/overfeeding, and to 4 degrees C. Fto/Ftm expression was reduced in mesenteric adipose tissue of mice segregating for the Ay, Lep ob, Lepr db, Cpe fat, or tub mutations, and there was a similar trend in other tissues. These effects were not due to adiposity per se. Hypothalamic Fto and Ftm expression were decreased by fasting in lean and obese animals and by cold exposure in lean mice. The fact that responses of Fto and Ftm expression to these manipulations were almost indistinguishable suggested that the genes might be coregulated. The putative overlapping regulatory region contains at least two canonical CUTL1 binding sites. One of these nominal CUTL1 sites includes rs8050136, a SNP associated with high body mass. The A allele of rs8050136 preferentially bound CUTL1[corrected] in human fibroblast DNA. 70% knockdown of CUTL1 expression in human fibroblasts decreased FTO and FTM expression by 90 and 65%, respectively. Animals and humans with various genetic interruptions of FTO or FTM have phenotypes reminiscent of aspects of the Bardet-Biedl obesity syndrome, a confirmed "ciliopathy." FTM has recently been shown to be a ciliary basal body protein.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Adiposidade/genética , Regulação da Expressão Gênica , Obesidade/genética , Oxo-Ácido-Liases/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Animais , Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/metabolismo , Células Cultivadas , Proteínas do Citoesqueleto , Modelos Animais de Doenças , Ingestão de Alimentos , Embrião de Mamíferos/metabolismo , Metabolismo Energético/genética , Jejum/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Hipotálamo/metabolismo , Hipotermia Induzida , Leptina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Oxigenases de Função Mista , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Obesidade/metabolismo , Oxo-Ácido-Liases/metabolismo , Proteínas/metabolismo , RNA Mensageiro/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Células Estromais/metabolismo , Fatores de Transcrição , TransfecçãoRESUMO
DNA microarray analysis has been used to investigate relative changes in the level of gene expression in the CNS, including changes that are associated with disease, injury, psychiatric disorders, drug exposure or withdrawal, and memory formation. We have used oligonucleotide microarrays to identify hypothalamic genes that respond to nutritional manipulation. In addition to commonly used microarray analysis based on criteria such as fold-regulation, we have also found that simply carrying out multiple t tests then sorting by P value constitutes a highly reliable method to detect true regulation, as assessed by real-time polymerase chain reaction (PCR), even for relatively low abundance genes or relatively low magnitude of regulation. Such analyses directly suggested novel mechanisms that mediate effects of nutritional state on neuroendocrine function and are being used to identify regulated gene products that may elucidate the metabolic pathology of obese ob/ob, lean Vgf-/Vgf-, and other models with profound metabolic impairments.