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Pell N, Garcia-Pras E, Gallego J, et al. Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis. Mol Metab. 2021;54:101388doi: 10.1016/j.molmet.2021.101388.
Pell, N., Garcia-Pras, E., Gallego, J., Naranjo-Suarez, S., Balvey, A., Suñer, C., Fernandez-Alfara, M., Chanes, V., Carbo, J., Ramirez-Pedraza, M., Reina, O., Thingholm, L., Bang, C., Rühlemann, M., Franke, A., Schierwagen, R., Rheinwalt, K. P., Trebicka, J., Mendez, R., & Fernandez, M. (2021). Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis. Molecular metabolism, 54101388. https://doi.org/10.1016/j.molmet.2021.101388
Pell, Nuria, et al. "Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis." Molecular metabolism vol. 54 (2021): 101388. doi: https://doi.org/10.1016/j.molmet.2021.101388
Pell N, Garcia-Pras E, Gallego J, Naranjo-Suarez S, Balvey A, Suñer C, Fernandez-Alfara M, Chanes V, Carbo J, Ramirez-Pedraza M, Reina O, Thingholm L, Bang C, Rühlemann M, Franke A, Schierwagen R, Rheinwalt KP, Trebicka J, Mendez R, Fernandez M. Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis. Mol Metab. 2021 Dec;54:101388. doi: 10.1016/j.molmet.2021.101388. Epub 2021 Nov 10. PMID: 34774811; PMCID: PMC8711066.
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Mol Metab. 2021 Dec;54:101388. doi: 10.1016/j.molmet.2021.101388. Epub 2021 Nov 10.

Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis.

Molecular metabolism

Nuria Pell, Ester Garcia-Pras, Javier Gallego, Salvador Naranjo-Suarez, Alexandra Balvey, Clara Suñer, Marcos Fernandez-Alfara, Veronica Chanes, Julia Carbo, Marta Ramirez-Pedraza, Oscar Reina, Louise Thingholm, Corinna Bang, Malte Rühlemann, Andre Franke, Robert Schierwagen, Karl P Rheinwalt, Jonel Trebicka, Raul Mendez, Mercedes Fernandez

Affiliations

  1. IDIBAPS Biomedical Research Institute, University of Barcelona, Barcelona, Spain.
  2. Institute for Research in Biomedicine (IRB), The Barcelona Institute of Science and Technology, Barcelona, Spain.
  3. Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, University Hospital Schleswig Holstein Campus Kiel, Kiel, Germany.
  4. Goethe University Frankfurt, Frankfurt, Germany.
  5. Franziskus Krankenhaus, Cologne, Germany.
  6. Institute for Research in Biomedicine (IRB), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
  7. IDIBAPS Biomedical Research Institute, University of Barcelona, Barcelona, Spain. Electronic address: [email protected].

PMID: 34774811 PMCID: PMC8711066 DOI: 10.1016/j.molmet.2021.101388

Abstract

OBJECTIVE: Obesity represents a growing health problem that is reaching pandemic dimensions and lacks effective cures, thus highlighting an urgent need for better mechanistic understanding and new therapeutic strategies. Unlike transcription, the function of translation in obesity has hardly been investigated. Here, we fill this knowledge gap by pinpointing a crucial function for gene regulation at the step of translation in diet-induced obesity.

METHODS: We performed studies with human adipose tissue, high-fat-diet-induced obese mice and rats, CPEB4-knockout mice, and adipocyte lines. Cells were transfected with small-interfering RNAs that knockdown CPEB4. Transcriptome-wide identification and validation of CPEB4 targets in adipocytes were obtained by RNA-protein coimmunoprecipitation and high-throughput sequencing. The effect of CPEB4 depletion on high-fat-diet-induced dysbiosis was determined by 16S ribosomal-RNA gene sequencing and microbiome bioinformatics.

RESULTS: We show that cytoplasmic polyadenylation element-binding protein 4 (CPEB4), which controls the translation of specific mRNAs by modulating their poly(A) tails, is highly expressed in visceral fat of obese but not lean humans and rodents (mice and rats), where it orchestrates an essential post-transcriptional reprogramming for aggravation of high-fat-diet-induced obesity. Mechanistically, CPEB4 overexpression in obese adipocytes activates the translation of factors essential for adipose tissue expansion (Cebpb, Stat5a) and adipocyte-intrinsic immune-like potential (Ccl2, Tlr4), as demonstrated by RNA-immunoprecipitation and high-throughput sequencing and experimentally validated in vivo. Consistently blocking CPEB4 production in knockout mice protects against diet-induced body weight gain and reduces adipose tissue enlargement and inflammation. In addition, the depletion of CPEB4 specifically in obese adipocytes using short hairpin RNAs decreases cell differentiation, lipid accumulation, and the proinflammatory and migratory capacity of macrophages. The absence of CPEB4 also attenuates high-fat diet-induced dysbiosis, shaping the microbiome composition toward a more beneficial profile, as shown by microbiome bioinformatics analysis.

CONCLUSION: Our study identifies CPEB4 as a driver and therapeutic target to combat obesity.

Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.

Keywords: Adipose tissue; Microbiome dysbiosis; Obesity; RNA-Binding proteins; Translation

Conflict of interest statement

Conflict of interest Authors declare that they have no competing interests.

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