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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.

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

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

Autors: 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

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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/).

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