Epac1 mediates thermogenesis and lipolysis in white adipose tissue via the p38γ-NFAT5 axis in a PKA-independent manner

Beige adipocytes in white adipose tissue (WAT) share similar functions as brown adipocytes by converting lipids into heat through thermogenesis, while lipolysis is considered as a prerequisite for the activation of non-shivering thermogenesis. β3-adrenergic receptor (β3-AR) agonist CL316,243 (CL) and cold exposure are known to enhance lipolysis and beiging of WAT in a protein kinase A (PKA)-dependent manner, while the role of PKA-independent pathways involved is still poorly understood. Here, we show that the exchange protein directly activated by cAMP 1 (Epac1), a downstream target of cAMP, mediates β3-AR activation to modulate thermogenesis and lipolysis in a PKA-independent manner. Upon CL treatment or cold exposure, both thermogenic and lipolytic responses were compromised in Epac1-deficient mice, as evidenced by reduced oxygen consumption, less beige adipocytes, lower body temperature, and decreased circulating glycerol. Additionally, in vitro beige adipogenesis with or without cAMP analog treatment was significantly impaired in Epac1-deficient mice. Mechanistically, reduced total and phosphorylated p38γ and decreased induction of nuclear factor activated in T cells 5 (NFAT5) were observed in Epac1-deficient mice, which may contribute to the defective beiging of WAT. However, WAT of wildtype and Epac1-deficient mice showed no significant induction difference in phosphorylation of hormone-sensitive lipase at PKA and AMP-activated protein kinase sites with PKA activator, and in vitro beige adipogenesis was not altered in Epac1-deficient mice in response to PKA activation, indicating that Epac1 mediates lipolysis and beige adipogenesis in a PKA-independent manner. Taken together, Epac1 mediates β3-AR-induced beiging and lipolysis of WAT via the p38γ-NFAT5 axis in a PKA-independent manner.