Adipocyte mTORC1 Suppresses Treg Cell Development and Browning of White Adipose Tissue through CRTC2/COX-2/PGs Pathway

Abstract

Adipose tissue (AT) contains abundant CD4+Foxp3+ regulatory T (Treg) cells; however, the physiological signals that control AT Treg cell and the role of AT Treg cell in thermogenesis have not been defined. Here we show that obesity activated mTORC1 signaling while decreased frequency of Treg cells in white adipose tissue (WAT), and adipose-specific inhibition of mTORC1 by raptor deficiency promoted development of Treg cells and beige adipocytes and protected mice against diet-induced reduction of Treg cells and beige adipocytes in WAT and diet-induced obesity. Mechanistically, mTORC1 signaling phosphorylated CREB regulated transcription coactivator 2 (CRTC2) and subsequently suppressed expression of cyclooxygenase 2 (COX-2) and secretion of prostaglandins (PGs) including PGI2, PGD2 and PGE2 in vivo and in adipocytes. Treatment of PGE2 but not PGI2 and PGD2 promoted differentiation and activation of Treg cells in vitro and in vivo. Pharmacological inhibition of COX-2 or blocking Treg cell by neutralization of CD25 attenuated mTORC1 inhibition-induced browning of white fat. Further, deficiency of Treg cell suppressed the inducing effect of PGE2 administration on thermogenic gene expression and oxygen consumption in inguinal and epididymal WAT. Taken together, these results uncover that adipocyte mTORC1 is a key regulator of Treg cell and beige adipocyte development in adipose tissue via CRTC2/COX-2/PGs pathway-dependent mechanisms. Disclosure X. Zhang: None. Y. Luo: None. X. Ding: None. C. Wang: None. X. Yang: None. M. Liu: None.