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

TY - JOUR

T1 - The GPR120 agonist TUG-891 promotes metabolic health by stimulating mitochondrial respiration in brown fat

AU - Schilperoort, Maaike

AU - van Dam, Andrea D

AU - Hoeke, Geerte

AU - Shabalina, Irina G

AU - Okolo, Anthony

AU - Hanyaloglu, Aylin C

AU - Dib, Lea H

AU - Mol, Isabel M

AU - Caengprasath, Natarin

AU - Chan, Yi-Wah

AU - Damak, Sami

AU - Miller, Anne Reifel

AU - Coskun, Tamer

AU - Shimpukade, Bharat

AU - Ulven, Trond

AU - Kooijman, Sander

AU - Rensen, Patrick Cn

AU - Christian, Mark

N1 - © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2018/3

Y1 - 2018/3

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.15252/emmm.201708047

DO - 10.15252/emmm.201708047

M3 - Journal article

C2 - 29343498

SN - 1757-4676

VL - 10

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 3

M1 - e8047

ER -