A link between FTO, ghrelin, and impaired brain food-cue responsivity.

Abstract

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 N6-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 N6-methyladenosine methylation, concomitantly increasing ghrelin mRNA and peptide levels. Furthermore, peripheral blood cells from AA human subjects exhibited increased FTO mRNA, reduced ghrelin mRNA N6-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.

• Authors: Efthimia Karra, Owen G O'Daly, Agharul I Choudhury, Ahmed Yousseif, Steven Millership, Marianne T Neary, William R Scott, Keval Chandarana, Sean Manning, Martin E Hess, Hiroshi Iwakura, Takashi Akamizu, Queensta Millet, Cigdem Gelegen, Megan E Drew, Sofia Rahman, Julian J Emmanuel, Steven C R Williams, Ulrich U Rüther, Jens C Brüning, Dominic J Withers, Fernando O Zelaya, Rachel L Batterham
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 123 Issue 8 Pg. 3539-51 (Aug 2013) ISSN: 1558-8238 [Electronic] United States
• PMID: 23867619 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ghrelin
• Proteins
• RNA, Messenger
• RPS14 protein, human
• Ribosomal Proteins
• Alpha-Ketoglutarate-Dependent Dioxygenase FTO
• FTO protein, human
• Acyltransferases
• MBOAT4 protein, human

Topics

• Acyltransferases (genetics, metabolism)
• Adolescent
• Adult
• Alpha-Ketoglutarate-Dependent Dioxygenase FTO
• Animals
• Appetite
• Brain (physiology)
• Eating (psychology)
• Food
• Functional Neuroimaging
• Gene Expression
• Gene Expression Regulation
• Genetic Association Studies
• Ghrelin (blood)
• HEK293 Cells
• Humans
• Magnetic Resonance Imaging
• Male
• Methylation
• Mice
• Mice, Knockout
• Polymorphism, Single Nucleotide
• Proteins (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Reward
• Ribosomal Proteins (genetics, metabolism)
• Young Adult