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

• Published in: Cell reports (Cambridge) Vol. 24; no. 12; pp. 3180 - 3193
• Main Authors: Zhang, Xing, Luo, Yan, Wang, Chunqing, Ding, Xiaofeng, Yang, Xin, Wu, Dandan, Silva, Floyd, Yang, Zijiang, Zhou, Qin, Wang, Lu, Wang, Xiaoqing, Zhou, Jianlin, Boyd, Nathan, Spafford, Michael, Burge, Mark, Yang, Xuexian O., Liu, Meilian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.09.2018; Elsevier
• Subjects: Adipocytes, Beige - cytology; Adipocytes, Beige - metabolism; Adipogenesis; adipose tissue; Animals; beige adipocyte; Cell Line; COX-2; CRTC2; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclooxygenase 2 - metabolism; Diet, High-Fat - adverse effects; Humans; Mice; mTORC1; Obesity - etiology; Obesity - genetics; Obesity - metabolism; prostaglandin; Prostaglandins - metabolism; Regulatory-Associated Protein of mTOR - genetics; Regulatory-Associated Protein of mTOR - metabolism; Signal Transduction; thermogenesis; Transcription Factors - metabolism; UCP1; CRTC2; thermogenesis; COX-2; prostaglandin; UCP1; adipose tissue; beige adipocyte; mTORC1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.08.055

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. [Display omitted] •mTORC1 is a potent regulator of white to beige adipogenesis•mTORC1 inhibition leads to WAT browning and occurs despite sympathetic denervation•COX-2 and prostaglandins are essential for browning of WAT in Raptor-deficient mice•mTORC1 suppresses COX-2/PG pathway via a CRTC2-dependent mechanism 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.