Zangerolamo Lucas, Carvalho Marina, Barbosa Helena C L
Obesity and Comorbidities Research Center, University of Campinas-UNICAMP, Campinas 13083-970, Sao Paulo, Brazil.
Int J Mol Sci. 2025 Jul 8;26(14):6547. doi: 10.3390/ijms26146547.
Over the past decades, bile acids have been recognized as important signaling molecules with significant roles in metabolic health and disease. Many of their beneficial effects are mediated through the activation of the Takeda G protein-coupled receptor 5 (TGR5), a G protein-coupled receptor ubiquitously expressed in both humans and animals. Upon activation, TGR5 stimulates adenylate cyclase, leading to increased cyclic adenosine monophosphate (cAMP) levels and subsequent activation of protein kinase A (PKA). PKA then phosphorylates and activates several downstream signaling pathways, including exchange protein directly activated by cAMP (EPAC), extracellular signal-regulated kinase 1/2 (ERK1/2), and protein kinase B (AKT). Through these pathways, TGR5 acts as a key molecular link between bile acid signaling and the regulation of energy metabolism. TGR5 activation has been associated with body weight loss in obese models, primarily by reducing food intake, enhancing thermogenesis in adipose tissue and muscle to increase energy expenditure, and improving insulin secretion. This review highlights recent advances in our understanding of TGR5 biology and critically examines its therapeutic potential, limitations, and controversies in the context of energy metabolism, offering new perspectives and opportunities for treating metabolic disorders.
在过去几十年中，胆汁酸已被公认为是在代谢健康和疾病中发挥重要作用的信号分子。它们的许多有益作用是通过激活武田G蛋白偶联受体5（TGR5）介导的，TGR5是一种在人类和动物中普遍表达的G蛋白偶联受体。激活后，TGR5刺激腺苷酸环化酶，导致环磷酸腺苷（cAMP）水平升高，随后激活蛋白激酶A（PKA）。PKA随后磷酸化并激活几个下游信号通路，包括直接由cAMP激活的交换蛋白（EPAC）、细胞外信号调节激酶1/2（ERK1/2）和蛋白激酶B（AKT）。通过这些通路，TGR5作为胆汁酸信号与能量代谢调节之间的关键分子纽带。在肥胖模型中，TGR5激活与体重减轻有关，主要是通过减少食物摄入、增强脂肪组织和肌肉中的产热以增加能量消耗，以及改善胰岛素分泌。本综述重点介绍了我们对TGR5生物学认识的最新进展，并在能量代谢背景下批判性地审视了其治疗潜力、局限性和争议，为治疗代谢紊乱提供了新的视角和机会。
