Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis
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 in...
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2021
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oai:doaj.org-article:86a68fa47e414fe0a0f7d694e72e98942021-11-28T04:31:19ZTargeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis2212-877810.1016/j.molmet.2021.101388https://doaj.org/article/86a68fa47e414fe0a0f7d694e72e98942021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2212877821002398https://doaj.org/toc/2212-8778Objective: 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.Nuria PellEster Garcia-PrasJavier GallegoSalvador Naranjo-SuarezAlexandra BalveyClara SuñerMarcos Fernandez-AlfaraVeronica ChanesJulia CarboMarta Ramirez-PedrazaOscar ReinaLouise ThingholmCorinna BangMalte RühlemannAndre FrankeRobert SchierwagenKarl P. RheinwaltJonel TrebickaRaul MendezMercedes FernandezElsevierarticleObesityTranslationRNA-Binding proteinsAdipose tissueMicrobiome dysbiosisInternal medicineRC31-1245ENMolecular Metabolism, Vol 54, Iss , Pp 101388- (2021) |
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DOAJ |
| collection |
DOAJ |
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EN |
| topic |
Obesity Translation RNA-Binding proteins Adipose tissue Microbiome dysbiosis Internal medicine RC31-1245 |
| spellingShingle |
Obesity Translation RNA-Binding proteins Adipose tissue Microbiome dysbiosis Internal medicine RC31-1245 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 Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Nuria Pell |
| title |
Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis |
| title_short |
Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis |
| title_full |
Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis |
| title_fullStr |
Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis |
| title_full_unstemmed |
Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis |
| title_sort |
targeting the cytoplasmic polyadenylation element-binding protein cpeb4 protects against diet-induced obesity and microbiome dysbiosis |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/86a68fa47e414fe0a0f7d694e72e9894 |
| work_keys_str_mv |
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