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

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 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.

Metabolic Reprogramming of Liver Fibrosis

“…For instance, TTP has been shown to regulate the mRNA of several cytokines and chemokines (including IL-17, TNFα, IL-6, IL-1β, and CXCL1-2) and in several cell lines (macrophages, lymphocytes, endothelial cells, and MFB) [ 126 , 140 , 153 ]. Of note, our studies highlight the role of CPEB4 in the stress resolution of obesity-driven fibrosis and CLD [ 97 , 146 , 159 , 160 , 161 ]. Thus, it is tempting to speculate that future studies in RBPs and liver diseases will help us to elucidate the mechanism by which fibrosis initiates and perpetuates its pathology leading to CLD.…”

“…CPEB4, for instance, is highly expressed in the liver and its essential role in the stress response during liver diseases has been recently reviewed [ 145 ]. Interestingly, recent studies from our group using a murine model of diet-induced obesity placed CPEB4 as an important regulator of adipose tissue expansion [ 146 ]. Thus, considering the sensitivity of HSCs to lipid biology, these data also suggest CPEB4 as an indirect contributor to the activated HSC phenotype.…”

An encyclopedia of enhancer-gene regulatory interactions in the human genome

“…This cell-type specificity is interesting because CPEB4 has shown low expression specificity across human tissues 31,32 . Previous studies show that CPEB4 knockdown inhibits terminal erythroid differentiation 33 and lipid accumulation in adipocytes 34 , but the variant associated with MCH is predicted to overlap an enhancer specific to hematopoietic progenitors and not observed in adipocytes. Other interesting examples at the TFRC, KIT and BCL11A loci are reported in Note S7 (Fig S7.2 ).…”

Translational Control in Liver Disease

“…Conversely, our lab has been working for the past years in studying the role of CPEB4 in high fat diet induced obesity ( Pell et al, 2021 ), and the results have elucidated another mechanism by which macrophages are altered by the adipose tissue, not previously described in literature. Indeed, CPEB4 drives a posttranscriptional reprogramming in adipocytes of white adipose tissue under obesity conditions.…”