Abstract
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 (HuRfl/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
Highlights
Obesity, a heterogeneous metabolic disease character ized by an excessive accumulation of body fat, is a rising economic burden in the United States as well as an obstacle to individual and societal health and longevity
The results presented demonstrate that mice with an adipocyte-specific deletion of Human antigen R (HuR) are leaner and display increased energy expenditure compared to their wild-type control littermates
This resulted in an impairment in adaptive thermogenesis in AdipoHuR−/- mice that is independent of uncoupling protein 1 (UCP1) expression
Summary
A heterogeneous metabolic disease character ized by an excessive accumulation of body fat, is a rising economic burden in the United States as well as an obstacle to individual and societal health and longevity. There is a current unmet need for effective obesity therapeutics, and stimulating energy expenditure in mitochondria-rich brown adi pose tissue (BAT) represents a promising strategy/ther apeutic target for safely increasing metabolic rate and reducing obesity. Unlike white adipose tissue (WAT), the primary role of which is to store energy in the form of lipid droplets, BAT is highly metabolically active, uncoupling mito chondrial ATP synthesis resulting in the generation of heat. The energy expenditure of human BAT can be enhanced through cold or adrenergic stimulation, similar to BAT in rodents [1,3,4,5,6], suggesting these processes could be manipulated for therapeutic benefit. The thermogenic uncoupling of mitochondrial ATP synthesis, which can account for up to 20% of total energy expenditure [7], is achieved by the uncoupling proteins (UCP). UCP1, expressed exclusively in BAT, is upregulated by coldinduced β3-adrenergic signalling, and is criti cally important for the regulation of BAT-mediated thermogenesis [6,8]
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