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.

Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis

“…1E-F). As we have previously shown a decrease in body weight in Adipo-HuR -/- mice (1), cardiac structural changes have been normalized to body weight. Together, these data are indicative of a state of compensated cardiac hypertrophy in Adipo-HuR -/- mice.…”

“…We previously reported RNA-seq analysis of HuR-dependent changes in BAT (1), but found nothing that would be obviously indicative of cardiovascular disease. Here, we again applied RNA-seq (with a statistical cutoff of a fold change of ≥ 1.5 and an FDR P value of ≤ 0.05) to identify transcriptome-wide HuR-dependent gene expression in scWAT.…”

“…RNA was isolated from cardiac and adipose tissue as previously described (1, 70) and RNA sequencing was done by the Cincinnati Children’s Hospital Medical Center (CCHMC) DNA Sequencing and Genotyping Core. Sequence read mapping, principal component analysis, and differential expression analysis was done using CLC Genomics Workbench (v. 20.0.2, Qiagen) as previously described (1, 24). Gene ontology analysis was done using the NIH DAVID Bioinformatics Functional Annotation Tool with an EASE score/P-value threshold of 0.05 as previously described (35, 36, 77).…”

“…Human antigen R (HuR) is a widely-expressed RNA binding protein that interacts with specific AU-rich domains in target mRNAs and directly regulates expression by modulating mRNA stability and/or translation (14). Our recently published work was among the first to show the in vivo role of HuR on adipocyte physiology (1). Two other groups have also recently shown roles for HuR in adipogenesis and lipolysis (48, 69).…”

“…Two other groups have also recently shown roles for HuR in adipogenesis and lipolysis (48, 69). We specifically showed that adipocyte-specific deletion of HuR in mice (Adipo-HuR -/- mice) resulted in a reduction in both WAT and BAT mass that was accompanied by a profound deficit in adaptive thermogenesis when subjected to acute cold challenge (1). Interestingly, Li et al recently showed an inverse correlation between HuR expression in subcutaneous WAT (scWAT) and obesity in human patients (48), suggesting a clinical link for HuR expression in metabolic syndrome and raising the question as to whether loss of HuR expression in adipose tissue may play a functional role in obesity associated co-morbidities such as CVD.…”