Journal
CELL REPORTS
Volume 24, Issue 12, Pages 3180-3193Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.08.055
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Funding
- NIDDK [DK110439]
- NIGMS [GM121176]
- American Diabetes Association [1-17-IBS-261]
- National Basic Research Program of China [2014CB910501]
- CTSC pilot award
- CoBRE pilot award [P30GM103400]
- RAC pilot awards
- UNMCCC pilot award at the University of New Mexico Health Sciences Center (UNMHSC)
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of General Medical Science
- American Diabetes Association
- American Heart Association
- National Basic Research Program of China
- University of New Mexico Health Sciences Center (UNMHSC)
- NIH from NIGMS [P20GM121176]
- [15GRNT2490018]
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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.
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