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The GPR120 agonist TUG‐891 promotes metabolic health by stimulating mitochondrial respiration in brown fat

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Schilperoort, Maaike, van Dam, Andrea D., Hoeke, Geerte, Shabalina, Irina G., Okolo, Anthony, Hanyaloglu, Aylin C., Dib, Lea H., Mol, Isabel M., Caengprasath, Natarin, Chan, Yi-Wah, Damak, Sami, Miller, Anne Reifel, Coskun, Tamer, Shimpukade, Bharat, Ulven, Trond, Kooijman, Sander, Rensen, Patrick C. N. and Christian, Mark (2018) The GPR120 agonist TUG‐891 promotes metabolic health by stimulating mitochondrial respiration in brown fat. EMBO Molecular Medicine, 10 (3). e8047. doi:10.15252/emmm.201708047

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Official URL: http://dx.doi.org/10.15252/emmm.201708047

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Abstract

Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein-coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120-mediated signaling in BAT. We found that activation of GPR120 by the selective agonist TUG-891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT. Stimulation of brown adipocytes in vitro with TUG-891 acutely induced O2 consumption, through GPR120-dependent and GPR120-independent mechanisms. TUG-891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist TUG-891 is a promising strategy to increase lipid combustion and reduce obesity.

Item Type: Journal Article
Subjects: R Medicine > RC Internal medicine
Divisions: Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology
Faculty of Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Brown adipose tissue, Obesity -- Prevention, G proteins -- Receptors, Cell receptors, Mitochondria, Lipids -- Metabolism
Journal or Publication Title: EMBO Molecular Medicine
Publisher: Wiley-Blackwell Publishing Ltd.
ISSN: 1757-4676
Official Date: 1 March 2018
Dates:
DateEvent
1 March 2018Published
17 January 2018Available
22 December 2017Accepted
23 May 2017Submitted
Volume: 10
Number: 3
Article Number: e8047
DOI: 10.15252/emmm.201708047
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
BB/H020233/1Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/P008879/1Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
DIABAT - HEALTH-F2-2011-278373FP7 Healthhttp://dx.doi.org/10.13039/100011272
UNSPECIFIEDGenesis Research Trusthttp://dx.doi.org/10.13039/100012156
11-116196Strategiske Forskningsrådhttp://dx.doi.org/10.13039/100007398
UNSPECIFIEDUniversiteit Leidenhttp://dx.doi.org/10.13039/501100001717
UNSPECIFIEDHartstichtinghttp://dx.doi.org/10.13039/501100002996
Lilly Research Award ProgramEli Lilly and Companyhttp://dx.doi.org/10.13039/100004312
CVON2011-9 GENIUSHartstichtinghttp://dx.doi.org/10.13039/501100002996
UNSPECIFIEDRembrandt Institute of Cardiovascular Science (Organisation)UNSPECIFIED

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