TC‐E 5003, a protein methyltransferase 1 inhibitor, activates the PKA‐dependent thermogenic pathway in primary murine and human subcutaneous adipocytes

TC‐E 5003 increases the expression of UCP1 in primary iWAT cells. TC‐E 5003 activates the downstream molecules of PKA signaling. Thermogenic effects of TC‐E 5003 are PRMT1‐ and β‐adrenergic receptor‐independent. TC‐E 5003 potently works in human SQ adipocytes isolated from multiple donors. We previously reported the involvement of protein arginine methyltransferase 1 (PRMT1) in adipocyte thermogenesis. Here, we investigate the effects of PRMT1 inhibitors on thermogenesis. Unexpectedly, we find that the PRMT1 inhibitor TC‐E 5003 (TC‐E) induces the thermogenic properties of primary murine and human subcutaneous adipocytes. TC‐E treatment upregulates the expression of Ucp1 and Fgf21 significantly and activates protein kinase A signaling and lipolysis in primary subcutaneous adipocytes from both mouse and humans. We further find that the thermogenic effects of TC‐E are independent of PRMT1 and beta‐adrenergic receptors. Our data indicate that TC‐E exerts strong effects on murine and human subcutaneous adipocytes by activating beige adipocytes via PKA signaling.