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, highlighting the 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 was obtained by RNA-protein coimmunoprecipitation and high-throughput sequencing. 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 a posttranscriptional reprogramming essential 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 for 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, depletion of CPEB4 specifically in obese adipocytes using short hairpin RNAs decreases cell differentiation, lipid accumulation and the proinflammatory and migratory capacity of macrophages. Absence of CPEB4 also attenuates high-fat diet-induced dysbiosis, shaping the microbiome composition towards a more beneficial profile, as shown by microbiome bioinformatic analysis. Conclusion Our study identifies CPEB4 as a driver and therapeutic target to combat obesity.