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HuR expression in adipose tissue mediates energy expenditure and acute thermogenesis independent of UCP1 expression.

ABSTRACT: The goal of this study was to define the functional role of adipocyte-specific expression of the RNA binding protein Human antigen R (HuR). Mice with an adipocyte-specific deletion of HuR (Adipo-HuR^-/- ) were generated by crossing HuR floxed (HuR^fl/fl ) mice with mice expressing adiponectin-driven cre-recombinase (Adipoq-cre). Our results show that Adipo-HuR^-/- mice display a lean phenotype compared to wild-type littermate controls. HuR deletion results in a diet-independent reduction in percent body fat composition along with an increase in energy expenditure. Functionally, Adipo-HuR^-/- mice show a significant impairment in acute adaptive thermogenesis (six hours at 4°C), but uncoupling protein 1 (UCP1) protein expression in brown adipose tissue (BAT) is unchanged compared to control. Pharmacological inhibition of HuR also results in a marked decline in core body temperature following acute cold challenge independent of UCP1 protein expression. Among the 588 HuR-dependent genes in BAT identified by RNA-seq analysis, gene ontology analysis shows a significant enrichment in mediators of calcium transport and signalling, almost all of which are decreased in Adipo-HuR^-/- mice compared to control. In conclusion, adipocyte expression of HuR plays a central role in metabolic homoeostasis and mediates UCP1-independent thermogenesis in BAT, potentially through post-transcriptional control of intracellular calcium transport.Abbreviations: Adipo-HuR^-/-: Adipocyte-specific HuR deletion mice; BAT: Brown adipose tissue; HuR: Human antigen R; UCP1: Uncoupling protein 1.

SUBMITTER: Anthony SR

PROVIDER: S-EPMC7469577 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This SuperSeries is composed of the SubSeries listed below.

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Tissue inhibitor of metalloproteinase-3 knockout mice exhibit enhanced energy expenditure through thermogenesis.

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CPEB2-dependent translation of long 3'-UTR Ucp1 mRNA promotes thermogenesis in brown adipose tissue

Project description:Expression of mitochondrial proton transporter Uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is essential for mammalian thermogenesis. While human UCP1 mRNA exists in a long form only, alternative polyadenylation creates two different isoforms in mice with 10% of UCP1 mRNA found in the long form (Ucp1L) and ~90% in the short form (Ucp1S). We generated a mouse model expressing only Ucp1S and found that it showed impaired thermogenesis due to a 60% drop in UCP1 protein levels, suggesting that Ucp1L is more efficiently translated than Ucp1S. In addition, we found that β3 adrenergic receptor signaling promoted the translation of mouse Ucp1L and human Ucp1 in a manner dependent on cytoplasmic polyadenylation element binding protein 2 (CPEB2). CPEB2-knockout mice showed reduced UCP1 levels and impaired thermogenesis in BAT, which was rescued by ectopic expression of CPEB2. Hence, long 3'-UTR Ucp1 mRNA translation activated by CPEB2 is likely conserved and important in humans to produce UCP1 for thermogenesis.

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Alternative Polyadenylation and Differential Regulation of <i>Ucp1</i>: Implications for Brown Adipose Tissue Thermogenesis Across Species.

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