Unraveling liver-derived signals against obesity and diabetes

新陈代谢在全身不同器官/组织之间协调和调节。这种协调的代谢调节显然对维持全身内环境平衡，特别是葡萄糖和能量代谢是必不可少的。因此，器官/组织之间的沟通是极其重要的，这种控制系统的干扰可能会导致代谢紊乱的发展。在这十年中，脂肪组织作为内分泌器官和疾病发展的贡献者的多功能性已经确立。然而，最近的一些研究表明，组织特异性基因敲除小鼠表现出意想不到的表型，这表明器官/组织之间存在许多未知形式的串扰。我们已经确定了几个由自主神经回路组成的系统，即代谢信息高速公路，它们在传递有关新陈代谢的器官间通信方面发挥着重要作用。传入肝迷走神经参与能量消耗和脂肪积累的发现就是一个例证。我们在肝脏中表达了PPAR_γ，导致脂肪组织脂肪分解增强，全身能量消耗增加。因此，肝脏迷走神经传入对肝脏脂肪堆积作出反应，将过量能量积聚的信息传递给大脑，从而增加交感神经流出，从而增加能量消耗。我们的发现表明，大脑从周围器官/组织获得各种代谢信息，导致全身组织/器官之间的协同代谢调节。此外，在长期摄入过量热量的情况下，这些系统似乎有助于代谢综合征的病理特征。因此，阐明这些调节系统可能有助于解开代谢稳态的潜在机制和代谢综合征的潜在发展。

Metabolism is coordinated and regulated among different organs/tissues throughout the body. This coordinated metabolic regulation is apparently essential for maintaining systemic homeostasis, particularly glucose and energy metabolism. Therefore, communication among organs/tissues is extremely important and perturbation of this control system may lead to the development of metabolic disorders. During this decade, the versatility of adipose tissue as an endocrine organ and as a contributor to disease development has been established. However, a number of recent studies have shown that tissue-specific knockout mice exhibit unexpected phenotypes, suggesting the presence of many as yet unknown forms of cross-talk among organs/tissues.We have identified several systems consisting of autonomic nerve circuits, i.e. metabolic information highways, which play important roles in conveying inter-organ communication regarding metabolism. This is exemplified by the discovery of involvement of the afferent hepatic vagus in energy expenditure and fat accumulation. We expressed PPAR_γ in the liver, resulting in enhanced lipolysis in fat tissue and increased systemic energy expenditure. Thus, in response to lipid accumulation in the liver, hepatic vagal afferents transmit information regarding excess energy accumulation to the brain, thereby increasing sympathetic outflow to enhance energy expenditure.Our findings indicate that the brain obtains a variety of metabolic information from peripheral organs/tissues, resulting in cooperative metabolic regulation among tissues/organs throughout the body. Furthermore, these systems appear to contribute to pathological features of the metabolic syndrome under the condition of long-term excess calorie intake. Thus, elucidation of these regulatory systems may facilitate unraveling the mechanisms underlying metabolic homeostasis and those underlying development of the metabolic syndrome.