Department of Genomic Drug Discovery Science, Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo-ku, Kyoto 606-8501, Japan.
Proc Natl Acad Sci U S A. 2011 May 10;108(19):8030-5. doi: 10.1073/pnas.1016088108. Epub 2011 Apr 25.
The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.
能量平衡的维持对生命至关重要，其失调会导致各种代谢紊乱。在进食状态下，哺乳动物以葡萄糖作为主要代谢燃料，膳食纤维在结肠细菌发酵产生的短链脂肪酸（SCFAs）也为每日能量需求贡献了相当大的比例。在饥饿和糖尿病等生酮状态下，肝脏从脂肪酸中产生的酮体被用作主要能源。为了平衡能量摄入，饮食过量和饥饿分别通过调节交感神经系统（SNS）的活性来增加或减少能量消耗。葡萄糖对代谢平衡的调节作用已得到广泛认可；然而，SCFAs 和酮体在维持能量平衡中的作用仍不清楚。在这里，我们表明 SCFAs 和酮体通过 GPR41（SCFAs 的 Gi/o 蛋白偶联受体）直接在交感神经节水平上调节 SNS 活性。GPR41 在小鼠和人类的交感神经节中表达最为丰富。丙酸盐通过 GPR41 促进交感神经输出。另一方面，在饥饿或糖尿病期间产生的酮体β-羟丁酸通过拮抗 GPR41 抑制 SNS 活性。药理学和 siRNA 实验表明，GPR41 介导的交感神经元激活涉及 Gβγ-PLCβ-MAPK 信号通路。SCFAs 和酮体对交感神经的调节与其对能量消耗的各自影响密切相关。这些发现确立了 SCFAs 和酮体直接调节 GPR41 介导的 SNS 活性，从而控制代谢平衡中身体的能量消耗。
