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Grant support

This work was supported by grants from the FEDER/Spanish Ministry of Science, Innovation and Universities (SAF2014-55473-R, SAF2017-87988-R, PID2020-118937RB-I00 MCIN/AEI/10.13039/501100011033, BES2015-071399 and PRE2018-083718 to MF; BFU2017-83561-P and PID2020-119533 GB-I00 to RM), and the Spanish Association Against Cancer (GCB15152955MEND), Worldwide Cancer Research Foundation (20_0284), World Cancer Research Fund International (IIG_FULL_ 2020_021), BBVA Foundation (28/2019), La Caixa Foundation (HR1800302), and La Marato TV3 Foundation (2019-0259) to MF and RM. IDIBAPS and IRB are supported by the CERCA Programme (Catalan Government). IRB is the recipient of a Severo Ochoa Award of Excellence from the Spanish Government. We also thank N. Prats from the Histopathology Facility at IRB, I. Crespo from the IDIBAPS Flow Cytometry and Cell Sorting Facility and A. Bosch from the UB Microscopy Facility for their assistance with analysis.

Analysis of institutional authors

Pell NAuthorGarcia-Pras EAuthorGallego JAuthorNaranjo-Suárez SAuthorBalvey AAuthorRamirez-Pedraza MAuthorFernandez M.Corresponding Author

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Article

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

Publicated to:Molecular Metabolism. 54 101388- - 2021-12-01 54(), DOI: 10.1016/j.molmet.2021.101388

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

Affiliations

Barcelona Inst Sci & Technol, Inst Res Biomed IRB, Barcelona, Spain - Author
Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Univ Hosp Schleswig Holstein, Campus Kiel, Kiel, Germany - Author
Franziskus Krankenhaus, Cologne, Germany - Author
Goethe Univ Frankfurt, Frankfurt, Germany - Author
Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Spain - Author
Univ Barcelona, 1DIBAPS Biomed Res Inst, Barcelona, Spain - Author
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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 dietinduced 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 highfat 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. (c) 2021 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords

adiposeadipose tissueangiogenesisdiversityexpressiongut microbiotahepatic steatosisinsulin-resistancelocimicrobiome dysbiosisrna-binding proteinstranslationtranslational controlAdipose tissueInflammatory-bowel-diseaseMicrobiome dysbiosisObesityRna-binding proteinsTranslation

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Molecular Metabolism due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2021, it was in position 17/146, thus managing to position itself as a Q1 (Primer Cuartil), in the category Endocrinology & Metabolism.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 2.14, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-27, the following number of citations:

  • WoS: 7
  • Scopus: 10
  • Europe PMC: 5

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-27:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 54.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 54 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 62.75.
  • The number of mentions on the social network X (formerly Twitter): 14 (Altmetric).
  • The number of mentions in news outlets: 7 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Germany.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Pell Vidal, Nuria) and Last Author (Fernández Lobato, Mercedes).

the author responsible for correspondence tasks has been Fernández Lobato, Mercedes.