PGE2‐EP3 axis promotes brown adipose tissue formation through stabilization of WTAP RNA methyltransferase

Abstract Brown adipose tissue (BAT) functions as a thermogenic organ and is negatively associated with cardiometabolic diseases. N 6 ‐methyladenosine (m 6 A) modulation regulates the fate of stem cells. Here, we show that the prostaglandin E 2 (PGE 2 )–E‐prostanoid receptor 3 (EP3) axis was activated during mouse interscapular BAT development. Disruption of EP3 impaired the browning process during adipocyte differentiation from pre‐adipocytes. Brown adipocyte‐specific depletion of EP3 compromised interscapular BAT formation and aggravated high‐fat diet‐induced obesity and insulin resistance in vivo . Mechanistically, activation of EP3 stabilized the Zfp410 mRNA via WTAP‐mediated m 6 A modification, while knockdown of Zfp410 abolished the EP3‐induced enhancement of brown adipogenesis. EP3 prevented ubiquitin‐mediated degradation of WTAP by eliminating PKA‐mediated ERK1/2 inhibition during brown adipocyte differentiation. Ablation of WTAP in brown adipocytes abrogated the protective effect of EP3 overexpression in high‐fat diet‐fed mice. Inhibition of EP3 also retarded human embryonic stem cell differentiation into mature brown adipocytes by reducing the WTAP levels. Thus, a conserved PGE 2 ‐EP3 axis promotes BAT development by stabilizing WTAP/Zfp410 signaling in a PKA/ERK1/2‐dependent manner.