HuR-dependent expression of RyR2 contributes to calcium-mediated thermogenesis in murine brown adipocytes

Several thermogenic pathways have been described in adipose tissue, including calcium-mediated thermogenesis in beige adipocytes. We have previously shown that adipocyte-specific deletion of the RNA binding protein human antigen R (HuR; Elavl1) results in thermogenic dysfunction. RNA sequencing revealed the downregulation of several calcium transport genes upon HuR deletion. The goal of this work was to define the HuR-dependent mechanisms of calcium driven thermogenesis in brown adipocytes. Brown adipose tissue (BAT)-specific HuR-deletion (BAT-HuR^-/-) mice have no changes in their body weight, glucose tolerance, adipose tissue weights, or lipid droplet size compared to control, but are cold intolerant following acute thermal challenge at 4 °C. We also found decreased expression of ryanodine receptor 2 (Ryr2) in BAT from BAT-HuR^-/- mice. We show that genetic deletion or pharmacological inhibition of HuR blunts both the increase in cytosolic calcium and the β-adrenergic-mediated heat generation in stromal vascular fraction (SVF)-derived primary brown adipocytes. Mechanistically, we show that HuR directly binds and reduces the decay rate of Ryr2 mRNA in brown adipocytes, and stabilization of Ryr2 via S107 rescues the observed changes. In conclusion, our results suggest that HuR-dependent control of Ryr2 expression plays a significant role in the thermogenic function of brown adipose tissue through modulation of sarcoendoplasmic-reticulum calcium cycling.