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

TY - JOUR

T1 - A link between FTO, ghrelin, and impaired brain food-cue responsivity

AU - Karra, Efthimia

AU - O'Daly, Owen G

AU - Choudhury, Agharul I

AU - Yousseif, Ahmed

AU - Millership, Steven

AU - Neary, Marianne T

AU - Scott, William R

AU - Chandarana, Keval

AU - Manning, Sean

AU - Hess, Martin E

AU - Iwakura, Hiroshi

AU - Akamizu, Takashi

AU - Millet, Queensta

AU - Gelegen, Cigdem

AU - Drew, Megan E

AU - Rahman, Sofia

AU - Emmanuel, Julian J

AU - Williams, Steven C R

AU - Rüther, Ulrich U

AU - Brüning, Jens C

AU - Withers, Dominic J

AU - Zelaya, Fernando O

AU - Batterham, Rachel L

PY - 2013/8/1

Y1 - 2013/8/1

N2 - 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.

AB - 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.

U2 - 10.1172/JCI44403

DO - 10.1172/JCI44403

M3 - Article

C2 - 23867619

VL - 123

SP - 3539

EP - 3551

JO - The Journal of clinical investigation

JF - The Journal of clinical investigation

IS - 8

M1 - N/A

ER -