Adipose mTORC1 Suppresses Prostaglandin Signaling and Beige Adipogenesis via the CRTC2-COX-2 Pathway

Summary: Beige adipocytes are present in white adipose tissue (WAT) and have thermogenic capacity to orchestrate substantial energy metabolism and counteract obesity. However, adipocyte-derived signals that act on progenitor cells to control beige adipogenesis remain poorly defined. Here, we show that adipose-specific depletion of Raptor, a key component of mTORC1, promoted beige adipogenesis through prostaglandins (PGs) synthesized by cyclooxygenase-2 (COX-2). Moreover, Raptor-deficient mice were resistant to diet-induced obesity and COX-2 downregulation. Mechanistically, mTORC1 suppressed COX-2 by phosphorylation of CREB-regulated transcription coactivator 2 (CRTC2) and subsequent dissociation of CREB to cox-2 promoter in adipocytes. PG treatment stimulated PKA and promoted differentiation of progenitor cells to beige adipocytes in culture. Ultimately, we show that pharmacological inhibition or suppression of COX-2 attenuated mTORC1 inhibition-induced thermogenic gene expression in inguinal WAT in vivo and in vitro. Our study identifies adipocyte-derived PGs as key regulators of white adipocyte browning, which occurs through mTORC1 and CRTC2. : Beige adipocytes, which develop in white adipose tissue (WAT), have become a promising avenue to counteract obesity. However, the repertoire of extracellular signals that control beige adipogenesis remains largely unknown. Here, Zhang et al. show that COX-2-mediated prostaglandins act as paracrine signals that orchestrate beige adipogenesis and are controlled by the mTORC1/CRTC2 pathway. Keywords: mTORC1, COX-2, CRTC2, UCP1, prostaglandin, beige adipocyte, adipose tissue, thermogenesi