Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis
| Autor: | Nuria Pell, Marcos Fernandez-Alfara, Andre Franke, Karl P. Rheinwalt, Malte C. Rühlemann, Salvador Naranjo-Suarez, Clara Suñer, Alexandra Balvey, Raúl Méndez, Jonel Trebicka, Mercedes Fernandez, Julia Carbo, Corinna Bang, Louise B. Thingholm, Oscar Reina, Ester Garcia-Pras, Javier Gallego, Marta Ramirez-Pedraza, Veronica Chanes, Robert Schierwagen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Translation Cytoplasmic polyadenylation element BMI body mass index GAPDH glyceraldehyde 3-phosphate dehydrogenase Adipose tissue RIP-Seq RNA-protein immunoprecipitation and high-throughput sequencing C/EBP CCAAT/enhancer binding protein STAT5A signal transducer and activator of transcription 5A chemistry.chemical_compound ZO-1 zonula occludens-1 GSEA gene set enrichment analysis HFD high fat diet Adipocyte CEBPB FFA free fatty acids Internal medicine Gene knockdown ND normal diet RNA-Binding proteins WAT white adipose tissue KLF2 Krüppel like factor 2 LBP lipopolysaccharide-binding protein VEGF vascular endothelial growth factor Cell biology UTR untranslated region PPAR-α peroxisome proliferator-activated receptor-α shRNA short hairpin RNA Original Article MCP1 monocyte chemoattractant protein-1 Female Adult DAPI 4 6-diamidino-2-phenylindole PCNA proliferating cell nuclear antigen CSF1 colony stimulating factor-1 Biology Diet High-Fat Polyadenylation Proinflammatory cytokine GLUT-4 glucose transporter type-4 CPEB cytoplasmic polyadenylation element binding protein UCP-1 uncoupling protein-1 CCL2 C–C motif chemokine ligand-2 medicine NEFA non-esterified fatty acids IPTG isopropyl β-D-1-thio-galactosidase Humans Microbiome Obesity Molecular Biology mGWAS microbiome genome-wide association studies GO gene ontology Microbiome dysbiosis Cell Biology JAM-A junctional adhesion molecule-A medicine.disease RC31-1245 TLR-4 Toll-like receptor-4 Gastrointestinal Microbiome chemistry IL10 interleukin-10 FMO fluorescent minus one Dysbiosis NAFLD nonalcoholic fatty liver disease |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 54, Iss, Pp 101388-(2021) |
| ISSN: | 2212-8778 |
| Popis: | 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. Highlights • CPEB4 expression is elevated in adipose tissue from obese patients and rodents. • CPEB4 overexpression is required for the abnormal obesity-associated phenotype. • Targeting CPEB4 reduces predisposition to diet-induced obesity. • Targeting CPEB4 alleviates obesity-associated microbiome dysbiosis. • CPEB4 is an attractive therapeutic target for treating obesity and its sequelae. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|