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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Research Article Metabolism

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 1

Hunger scores, plasma acyl-ghrelin levels, and appeal of hedonic images in TT and AA subjects.

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Hunger scores, plasma acyl-ghrelin levels, and appeal of hedonic images ...
(A) Standard test meal study protocol. On the day prior to the study, subjects consumed the same evening meal at 20:00, then fasted and drank only water. On the study day, a venous cannula was inserted into a left forearm vein, and a period of 1 hour was allowed for acclimatization. At t0, a baseline blood sample and appetite VAS were taken. Subjects were then given a standard test meal to consume within 20 minutes. Blood samples and appetite VAS were taken at t20 and t30 and every 30 minutes thereafter until t180. (B–D) Postprandial responses in 10 TT (blue squares) and 10 AA (red circles) adiposity-matched subjects to a meal at t0. (B) Δ Hunger, (C) Δ plasma acyl-ghrelin concentrations, and (D) AUC Δ acyl-ghrelin in TT (blue bar) and AA (red bar) subjects. (E–G) fMRI fed–study day postprandial responses in 12 TT (blue squares) and 12 AA (red circles) adiposity-matched subjects to a meal at t0. (E) Δ Hunger, (F) Δ plasma acyl-ghrelin concentrations, and (G) AUC Δ acyl-ghrelin suppression in TT (blue bar) and AA (red bar) subjects. (H) Postprandial appeal ratings of hedonic, high-calorie food images from 12 TT (blue bar) and 12 AA (red bar) fMRI study subjects. (I and J) Combined postprandial (I) AUC Δ hunger reduction and (J) AUC Δ acyl-ghrelin suppression in 22 TT (blue bars) and 22 AA (red bars) subjects. Data are presented as the mean ± SEM. *P < 0.05; **P < 0.01.