A link between FTO, ghrelin, and impaired brain food-cue responsivity
| Autor: | Cigdem Gelegen, Martin E. Hess, William R. Scott, Keval Chandarana, Agharul I. Choudhury, Steven Millership, Ulrich Rüther, Rachel L. Batterham, Ahmed Yousseif, Queensta Millet, Dominic J. Withers, Efthimia Karra, Fernando Zelaya, Julian J. Emmanuel, Marianne T. Neary, Steven Williams, Megan E. Drew, Sean Manning, Jens C. Brüning, Owen O'Daly, Takashi Akamizu, Hiroshi Iwakura, Sofia Rahman |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Ribosomal Proteins medicine.medical_specialty Adolescent media_common.quotation_subject Alpha-Ketoglutarate-Dependent Dioxygenase FTO Appetite Gene Expression Biology Methylation Polymorphism Single Nucleotide Eating Mice Young Adult Reward Internal medicine Orexigenic Gene expression medicine Animals Humans RNA Messenger Genetic Association Studies media_common Regulation of gene expression Mice Knockout Functional Neuroimaging digestive oral and skin physiology nutritional and metabolic diseases Brain Proteins General Medicine medicine.disease Obesity Magnetic Resonance Imaging Ghrelin Endocrinology HEK293 Cells Gene Expression Regulation Food Brain stimulation reward Acyltransferases medicine.drug |
| Zdroj: | The Journal of clinical investigation. 123(8) |
| ISSN: | 1558-8238 |
| Popis: | Polymorphisms in the fat mass and obesity-associated gene (FTO) are associated with human obesity and obesity-prone behaviors, including increased food intake and a preference for energy-dense foods. FTO demethylates N 6 -methyladenosine, a potential regulatory RNA modification, but the mechanisms by which FTO predisposes humans to obesity remain unclear. In adiposity-matched, normal-weight humans, we showed that subjects homozygous for the FTO “obesity-risk” rs9939609 A allele have dysregulated circulating levels of the orexigenic hormone acyl-ghrelin and attenuated postprandial appetite reduction. Using functional MRI (fMRI) in normal-weight AA and TT humans, we found that the FTO genotype modulates the neural responses to food images in homeostatic and brain reward regions. Furthermore, AA and TT subjects exhibited divergent neural responsiveness to circulating acyl-ghrelin within brain regions that regulate appetite, reward processing, and incentive motivation. In cell models, FTO overexpression reduced ghrelin mRNA N 6 -methyladenosine methylation, concomitantly increasing ghrelin mRNA and peptide levels. Furthermore, peripheral blood cells from AA human subjects exhibited increased FTO mRNA, reduced ghrelin mRNA N 6 -methyladenosine methylation, and increased ghrelin mRNA abundance compared with TT subjects. Our findings show that FTO regulates ghrelin, a key mediator of ingestive behavior, and offer insight into how FTO obesity-risk alleles predispose to increased energy intake and obesity in humans. |
| Databáze: | OpenAIRE |
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