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

Xing Zhang; Yan Luo; Chunqing Wang; Xiaofeng Ding; Xin Yang; Dandan Wu; Floyd Silva; Zijiang Yang; Qin Zhou; Lu Wang; Xiaoqing Wang; Jianlin Zhou; Nathan Boyd; Michael Spafford; Mark Burge; Xuexian O. Yang; Meilian Liu

Cell Reports (Sep 2018)

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

Xing Zhang,
Yan Luo,
Chunqing Wang,
Xiaofeng Ding,
Xin Yang,
Dandan Wu,
Floyd Silva,
Zijiang Yang,
Qin Zhou,
Lu Wang,
Xiaoqing Wang,
Jianlin Zhou,
Nathan Boyd,
Michael Spafford,
Mark Burge,
Xuexian O. Yang,
Meilian Liu

Affiliations

Xing Zhang: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, Hunan, China
Yan Luo: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
Chunqing Wang: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Xiaofeng Ding: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, Hunan, China
Xin Yang: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Dandan Wu: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Floyd Silva: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Zijiang Yang: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Qin Zhou: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Lu Wang: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Xiaoqing Wang: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
Jianlin Zhou: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, Hunan, China
Nathan Boyd: Department of Surgery, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Michael Spafford: Department of Surgery, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Mark Burge: Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Xuexian O. Yang: Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Meilian Liu: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Corresponding author

Journal volume & issue: Vol. 24, no. 12
pp. 3180 – 3193

Abstract

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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, thermogenesis

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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