Journal article
cAMP-inducible coactivator CRTC3 attenuates brown adipose tissue thermogenesis
Proceedings of the National Academy of Sciences - PNAS, Vol.115(23), pp.E5289-E5297
05/21/2018
DOI: 10.1073/pnas.1805257115
PMCID: PMC6003335
PMID: 29784793
Abstract
In response to cold exposure, placental mammals maintain body temperature by increasing sympathetic nerve activity in brown adipose tissue (BAT). Triggering of β-adrenergic receptors on brown adipocytes stimulates thermogenesis via induction of the cAMP/PKA pathway. Although cAMP response element-binding protein (CREB) and its coactivators-the cAMP-regulated transcriptional coactivators (CRTCs)-mediate transcriptional effects of cAMP in most tissues, other transcription factors such as ATF2 appear critical for induction of thermogenic genes by cAMP in BAT. Brown adipocytes arise from Myf5-positive mesenchymal cells under the control of PRDM16, a coactivator that concurrently represses differentiation along the skeletal muscle lineage. Here, we show that the CREB coactivator CRTC3 is part of an inhibitory feedback pathway that antagonizes PRDM16-dependent differentiation. Mice with a knockout of CRTC3 in BAT (BKO) have increased cold tolerance and reduced adiposity, whereas mice overexpressing constitutively active CRTC3 in adipose tissue are more cold sensitive and have greater fat mass. CRTC3 reduced sympathetic nerve activity in BAT by up-regulating the expression of miR-206, a microRNA that promotes differentiation along the myogenic lineage and that we show here decreases the expression of VEGFA and neurotrophins critical for BAT innervation and vascularization. Sympathetic nerve activity to BAT was enhanced in BKO mice, leading to increases in catecholamine signaling that stimulated energy expenditure. As reexpression of miR-206 in BAT from BKO mice reversed the salutary effects of CRTC3 depletion on cold tolerance, our studies suggest that small-molecule inhibitors against this coactivator may provide therapeutic benefit to overweight individuals.
Details
- Title: Subtitle
- cAMP-inducible coactivator CRTC3 attenuates brown adipose tissue thermogenesis
- Creators
- Young-Sil Yoon - Peptide Biology Laboratories, Salk Institute, La Jolla, CA 92037Wen-Wei Tsai - Peptide Biology Laboratories, Salk Institute, La Jolla, CA 92037Sam Van de Velde - Peptide Biology Laboratories, Salk Institute, La Jolla, CA 92037Zhijiang Chen - Peptide Biology Laboratories, Salk Institute, La Jolla, CA 92037Kuo-Fen Lee - Peptide Biology Laboratories, Salk Institute, La Jolla, CA 92037Donald A Morgan - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242Kamal Rahmouni - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242Shigenobu Matsumura - Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, 606-8502 Kyoto, JapanEzra Wiater - Peptide Biology Laboratories, Salk Institute, La Jolla, CA 92037Youngsup Song - Department of Medicine, Ulsan University School of Medicine, Asan Medical Center, Song Pa-gu, 138-736 Seoul, Republic of KoreaMarc Montminy - Peptide Biology Laboratories, Salk Institute, La Jolla, CA 92037; montminy@salk.edu
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.115(23), pp.E5289-E5297
- Publisher
- United States
- DOI
- 10.1073/pnas.1805257115
- PMID
- 29784793
- PMCID
- PMC6003335
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- DOI: 10.13039/100000002, name: HHS | National Institutes of Health, award: R01 DK083834; DOI: 10.13039/100007028, name: Leona M. and Harry B. Helmsley Charitable Trust, award: 2012-PG-MED002; DOI: 10.13039/501100003625, name: Ministry of Health and Welfare, award: HI11C1941; DOI: 10.13039/100000049, name: HHS | NIH | National Institute on Aging, award: AG047669; DOI: 10.13039/100000025, name: HHS | NIH | National Institute of Mental Health, award: MH114831; DOI: 10.13039/100000052, name: HHS | NIH | NIH Office of the Director, award: OD023076; DOI: 10.13039/100000054, name: HHS | NIH | National Cancer Institute, award: CA014195
- Language
- English
- Date published
- 05/21/2018
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040278702771
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