脂肪组织 mTORC1 通过 CRTC2-COX-2 通路抑制前列腺素信号和米色脂肪生成。
Adipose mTORC1 Suppresses Prostaglandin Signaling and Beige Adipogenesis via the CRTC2-COX-2 Pathway.
机构信息
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.
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.
出版信息
Cell Rep. 2018 Sep 18;24(12):3180-3193. 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.
米色脂肪细胞存在于白色脂肪组织（WAT）中，具有产热能力，可以协调大量能量代谢并抵抗肥胖。然而，脂肪细胞衍生的信号作用于祖细胞以控制米色脂肪生成仍未得到很好的定义。在这里，我们表明，脂肪特异性敲除雷帕霉素靶蛋白复合物 1（mTORC1）的关键组成部分 Raptor，通过环氧化酶-2（COX-2）合成的前列腺素（PGs）促进米色脂肪生成。此外，Raptor 缺陷小鼠对饮食诱导的肥胖和 COX-2 下调具有抗性。在机制上，mTORC1 通过磷酸化 CREB 调节转录共激活因子 2（CRTC2）来抑制 COX-2，随后 CREB 与脂肪细胞中 cox-2 启动子分离。PG 处理刺激蛋白激酶 A，并促进祖细胞在培养物中分化为米色脂肪细胞。最终，我们表明，药理学抑制或抑制 COX-2 可减弱体内和体外腹股沟 WAT 中 mTORC1 抑制诱导的产热基因表达。我们的研究确定了脂肪细胞衍生的 PGs 是白色脂肪细胞褐变的关键调节剂，这是通过 mTORC1 和 CRTC2 发生的。
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