HuR Mediates Thermogenic Metabolism in Brown Adipose Tissue Through Control of Sarco‐Endoplasmic Calcium Cycling

Abstract

Obesity is classified by the World Health Organization as one of eight principle causes of preventable chronic disease and is directly associated with decreased life expectancy due to increased risk of associated comorbidities. Brown adipose tissue (BAT) is a thermogenically active, endocrine organ regulating both glucose homeostasis and heat production, and the ability to induce BAT‐mediated energy expending represents a potential therapeutic avenue to reduce obesity.We recently showed that the RNA‐binding protein HuR (Human antigen R) plays a functional role in BAT‐mediated thermogenic metabolism. RNA sequencing analysis from mice with an adipocyte‐specific deletion of HuR (Adipo‐HuR‐/‐) revealed a BAT‐specific decrease in the expression of many genes responsible for sarco‐endoplasmic reticulum (SER) calcium cycling, including SERCA1a, RyR1, RyR2, and additional RyR complex proteins such as triadin, junctin, and CASR. Canonical thermogenesis in BAT occurs through uncoupling protein 1 (UCP1). However, several UCP1‐independent energy expending cycles, including intracellular calcium transport, have also been shown to regulate thermogenesis. SER calcium cycling has recently been established as a thermogenic mechanism in beige adipose tissue, but its functional contributions to thermogenesis in BAT have not yet been fully elucidated.To determine if the HuR‐dependent changes in SER calcium cycles manifest as a functional change in SER loading/cycling in BAT, we show that decreased cytosolic intracellular calcium levels in BAT isolated from Adipo‐HuR‐/‐mice. Additionally, we show that HuR is activated acutely downstream of beta‐adrenergic stimulation in BAT, and deletion of HuR blunts adrenergic‐induced increases in intracellular calcium. Furthermore, HuR directly binds RyR2 mRNA in brown adipocytes and regulates RyR2 expression through RNA stabilization. Taken together, this growing body of work suggests an important role for HuR in mediating thermogenesis through modulation of SER calcium cycling in brown adipose tissue.