Role of RNA binding protein HuR in the regulation of adaptive thermogenesis

Abstract

Brown adipose tissue (BAT) plays a key role in the regulated production of heat in response to cold temperatures, known as adaptive thermogenesis. While the transcriptional mechanisms underlying the thermogenic function of BAT has been widely studied, the role of posttranscriptional processes in BAT thermogenesis remain largely unexplored. RNA binding proteins are central in controlling multiple aspects of posttranscriptional RNA biology. Here, we identify brown fat HuR as a critical regulator of adaptive thermogenesis. Mice with adipocyte-specific HuR deletion (HuRAKO) were unable to increase energy expenditure in response to a cold challenge, resulting in marked hypothermia. The observed elevation in serum creatine kinase activity in cold-exposed HuRAKO mice implies the intact functionality of muscle shivering thermogenesis. However, failure of those mice to increase energy expenditure upon β3-adrenoreceptor agonist treatment indicates a defect in thermogenic BAT. In addition, HuR deletion or inhibition in brown adipocytes caused impaired mitochondrial respiration. RNA sequencing data revealed that the loss of HuR led to downregulation of genes associated with TCA cycle, β-oxidation, and mTORC1 signaling in BAT. The partial rescue of hypothermia observed in HuRAKO mice upon pharmacological activation of mTORC1 suggests that mTORC1 signaling may potentially mediate the impact of HuR on brown fat thermogenesis. Our findings reveal an essential role for RNA binding protein HuR in thermogenic programs of the brown adipocyte and highlight the importance of posttranscriptional processes in brown fat thermogenesis.