Central anorexigenic actions of bile acids are mediated by TGR5.
Central anorexigenic actions of bile acids are mediated by TGR5.
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胆汁酸的中枢缺氧作用是由TGR5介导的。
DOI：
10.1038/s42255-021-00398-4
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发表时间：
2021-05
影响因子：
20.8
通讯作者：
Schoonjans K
中科院分区：
文献类型：
--
作者：
Perino A;Velázquez-Villegas LA;Bresciani N;Sun Y;Huang Q;Fénelon VS;Castellanos-Jankiewicz A;Zizzari P;Bruschetta G;Jin S;Baleisyte A;Gioiello A;Pellicciari R;Ivanisevic J;Schneider BL;Diano S;Cota D;Schoonjans K
胆汁酸（BAs）是一种信号分子，在生理和病理过程中介导各种细胞反应。一些研究报告称，BAs可以在大脑中检测到，但它们在中枢神经系统中的生理作用仍然很大程度上未知。本研究表明，餐后BAs可以到达大脑，并通过TGR5激活控制生理进食的负反馈回路，TGR5是一种g蛋白偶联受体，可被多种共轭和非共轭BAs激活，是一种已知的外周代谢调节剂，，，，-。值得注意的是，外周或中央给药BA混合物或TGR5特异性BA模拟物（INT-777）在野生型小鼠中产生厌食作用，而全身、神经元特异性或刺鼠相关肽神经元TGR5缺失导致食物摄入量显著增加。因此，短期激活TGR5后，促氧肽的表达和分泌减少。体外研究表明，rho - rock - actin重塑途径的激活以tgr5依赖的方式减少了氧源性豚鼠相关肽/神经肽Y （AgRP/NPY）的释放。综上所述，这些数据确定了一个信号级联，通过该信号级联，BAs在禁食和进食之间的过渡中发挥急性作用，并启动向饱腹感的转换，揭示了以前未被认识到的由BAs在中枢神经系统中介导的生理反馈作用。
Bile acids (BAs) are signalling molecules that mediate various cellular responses in both physiological and pathological processes. Several studies report that BAs can be detected in the brain, yet their physiological role in the central nervous system is still largely unknown. Here we show that postprandial BAs can reach the brain and activate a negative-feedback loop controlling satiety in response to physiological feeding via TGR5, a G-protein-coupled receptor activated by multiple conjugated and unconjugated BAs and an established regulator of peripheral metabolism, , , , –. Notably, peripheral or central administration of a BA mix or a TGR5-specific BA mimetic (INT-777) exerted an anorexigenic effect in wild-type mice, while whole-body, neuron-specific or agouti-related peptide neuronal TGR5 deletion caused a significant increase in food intake. Accordingly, orexigenic peptide expression and secretion were reduced after short-term TGR5 activation. In vitro studies demonstrated that activation of the Rho–ROCK–actin-remodelling pathway decreases orexigenic agouti-related peptide/neuropeptide Y (AgRP/NPY) release in a TGR5-dependent manner. Taken together, these data identify a signalling cascade by which BAs exert acute effects at the transition between fasting and feeding and prime the switch towards satiety, unveiling a previously unrecognized role of physiological feedback mediated by BAs in the central nervous system.
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