Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
EMBO Mol Med. 2018 Mar;10(3). doi: 10.15252/emmm.201708047.
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 with TUG-891 acutely induced O 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.
棕色脂肪组织（BAT）的激活可刺激成年人的能量消耗，使其成为对抗肥胖及相关疾病的有吸引力的靶点。最近的研究表明，G 蛋白偶联受体 120（GPR120）在 BAT 产热中起作用。在这里，我们研究了 GPR120 激动剂的治疗潜力，并探讨了 BAT 中的 GPR120 介导的信号转导。我们发现，选择性激动剂 TUG-891 激活 GPR120 可在 C57Bl/6J 小鼠中急性增加脂肪氧化并降低体重和脂肪量。这些作用与棕色脂肪细胞脂质含量降低和 BAT 对营养物质的摄取增加一致，证实了 BAT 活性的增加。与这些观察结果一致，GPR120 缺乏会降低 BAT 中参与营养物质处理的基因表达。用 TUG-891 刺激棕色脂肪细胞可急性诱导耗氧量增加，这是通过 GPR120 依赖和非依赖机制实现的。TUG-891 不仅刺激 GPR120 信号转导，导致细胞内钙释放、线粒体去极化和线粒体分裂，还激活 UCP1。总的来说，这些数据表明，用 GPR120 激动剂 TUG-891 激活棕色脂肪细胞是增加脂肪燃烧和减少肥胖的一种很有前途的策略。
