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miRNA signatures associated with vulnerability to food addiction in mice and humans
Alejandra García-Blanco, … , Elena Martín-García, Rafael Maldonado
Alejandra García-Blanco, … , Elena Martín-García, Rafael Maldonado
Published March 29, 2022
Citation Information: J Clin Invest. 2022;132(10):e156281. https://doi.org/10.1172/JCI156281.
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Research Article Neuroscience

miRNA signatures associated with vulnerability to food addiction in mice and humans

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Abstract

Food addiction is characterized by a loss of behavioral control over food intake and is associated with obesity and other eating disorders. The mechanisms underlying this behavioral disorder are largely unknown. We aimed to investigate the changes in miRNA expression promoted by food addiction in animals and humans and their involvement in the mechanisms underlying the behavioral hallmarks of this disorder. We found sharp similitudes between miRNA signatures in the medial prefrontal cortex (mPFC) of our animal cohort and circulating miRNA levels in our human cohort, which allowed us to identify several miRNAs of potential interest in the development of this disorder. Tough decoy (TuD) inhibition of miRNA-29c-3p in the mouse mPFC promoted persistence of the response and enhanced vulnerability to developing food addiction, whereas miRNA-665-3p inhibition promoted compulsion-like behavior and also enhanced food addiction vulnerability. In contrast, we found that miRNA-137-3p inhibition in the mPFC did not lead to the development of food addiction. Therefore, miRNA-29c-3p and miRNA-665-3p could be acting as protective factors with regard to food addiction. We believe the elucidation of these epigenetic mechanisms will lead to advances toward identifying innovative biomarkers and possible future interventions for food addiction and related disorders based on the strategies now available to modify miRNA activity and expression.

Authors

Alejandra García-Blanco, Laura Domingo-Rodriguez, Judit Cabana-Domínguez, Noèlia Fernández-Castillo, Laura Pineda-Cirera, Jordi Mayneris-Perxachs, Aurelijus Burokas, Jose Espinosa-Carrasco, Silvia Arboleya, Jessica Latorre, Catherine Stanton, Bru Cormand, Jose-Manuel Fernández-Real, Elena Martín-García, Rafael Maldonado

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Figure 1

Extreme subpopulations of addicted and nonaddicted mice were selected among mice trained with chocolate-flavored pellets.

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Extreme subpopulations of addicted and nonaddicted mice were selected am...
(A) Timeline of the experimental sequence. (B) Operant conditioning maintained by chocolate-flavored or standard chow (SC) pellets. Mice trained with chocolate increased the number of reinforcers in 1 hour during FR5 daily sessions compared with mice trained with SC (data indicate the mean ± SEM; repeated-measures ANOVA; ***P < 0.001, pellet effect and pellets per session). (C–E) The 3 addiction-like criteria for the SC and chocolate-trained groups in the late period. (C) Persistence of response (Mann-Whitney U, *P < 0.05). (D) Motivation (Mann-Whitney U, ***P < 0.001). (E) Compulsion-like behavior. The dashed horizontal lines indicate the 75th percentile of the distribution of the chocolate-trained group. It was used as a threshold for considering a mouse positive for 1 criterion. (F) Percentage of addicted and nonaddicted mice trained with chocolate and SC pellets classified in the late period (χ2 test, ***P < 0.001). n = 51 mice trained with chocolate pellets; n = 7 mice trained with SC. (G–J) Tests for the 4 phenotypic traits in the late period for the chocolate-trained group, divided into addicted (A) and nonaddicted (NA) mice. (G) Impulsivity (Student’s t test, ***P < 0.001). (H) Cognitive flexibility (Mann Whitney U, *P < 0.05 and **P < 0.01. (I) Appetitive cue reactivity. Increased active response after presentation of the cue light (Mann-Whitney U, *P < 0.05). (J) Aversive cue reactivity. The number of nonreinforced active responses after the shock test with the same discriminative stimulus (grid floor) for the shock test. Pressing the active lever had no consequences: no shock, no pellets, and no cue light (Student’s t test, *P < 0.05). (K) Pellet intake and (L) body weight for mice classified as addicted or nonaddicted among those trained with chocolate pellets. n = 38 addicted mice; n = 13 nonaddicted mice trained with chocolate pellets. Data are presented as individual values with the IQR. Statistical details are included in Supplemental Table 10.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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