A link between FTO, ghrelin, and impaired brain food-cue responsivity
Efthimia Karra, … , Fernando O. Zelaya, Rachel L. Batterham
Efthimia Karra, … , Fernando O. Zelaya, Rachel L. Batterham
Published July 15, 2013
Citation Information: J Clin Invest. 2013;123(8):3539-3551. https://doi.org/10.1172/JCI44403.
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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

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Figure 4

Modulatory effects of acyl-ghrelin on BOLD responses in the fed state.

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Modulatory effects of acyl-ghrelin on BOLD responses in the fed state. (...
(A–D and G) Axial slices with superimposed group activity. MOG, middle occipital gyrus. (A–D) Brain regions where the TT and AA groups significantly differed in their relationship between food-related (all food greater than non-food) BOLD response and postprandial circulating acyl-ghrelin suppression (t0–t54). P < 0.05, FWE corrected. The left side of each panel is the left side of the brain. z is the MNI space z coordinate of the axial slice. T color scale reflects the T score of the interaction. (E and F) Regression plots between food-related BOLD response and circulating postprandial acyl-ghrelin suppression (t0–t54) in TT (blue, open squares) and AA (red, open circles) subjects. Positive regression and negative coefficients (β) were found in the TT (E) and AA (F) groups, respectively. Plotted coefficients were extracted from the cluster peak within the left cuneus (MNI space x, y, and z coordinates for the peak cluster voxel cluster [–12, –92, 28]). (G) Right caudate nucleus where the TT and AA groups exhibited a divergent relationship between BOLD response to hedonic food images and postprandial circulating acyl-ghrelin suppression (t0–t54). (H and I) Regression plots between BOLD response to hedonic food images and circulating postprandial ghrelin suppression in TT (blue, open squares) and AA (red, open circles) subjects. Negative and positive βs were found in the TT (H) and AA (I) groups, respectively. Plotted coefficients were extracted from the cluster peak within the right caudate nucleus (MNI space x, y, and z coordinates for the peak cluster voxel [22, 8, 18].