PNAS

评语： 

中医理论中经络、五脏六腑在运行过程中存在昼夜节律，本文通过质谱研究为肝脏代谢节律提供了有力的证据，也为代谢器官的中枢调控机制提供新的视角；同时，本文也扩展了多巴胺系统除经典奖赏功能之外的作用，丰富了领域内对多巴胺系统调控肝脏节律的认知。另外可卡因损伤肝脏代谢节律的表型也提示成瘾患者代谢紊乱的可能机制。本文的重要意义在于引发更多关于代谢器官节律和功能神经机制的思考，未来可以对肝脏代谢节律的神经环路机制、分子机制展开更为细致的研究。

关键词： 

medium spiny neurons (MSNs)；dopamine D2 receptor；liver；metabolomic

文章链接 ： 

https://doi.org/10.1073/pnas.2117113119

Abstract

The circadian clock is tightly intertwined with metabolism and relies heavily on multifaceted interactions between organ systems to maintain proper timing. Genetic and/or environmental causes can disrupt communication between organs and alter rhythmic activities. Substance use leads to altered dopamine signaling followed by reprogramming of circadian gene expression and metabolism in the reward system. However, whether altered dopamine signaling in the brain affects circadian metabolism in peripheral organs has not been fully explored. We show that dopamine D2 receptors (D2R) in striatal medium spiny neurons (MSNs) play a key role in regulating diurnal liver metabolic activities. In addition, drugs that increase dopamine levels, such as cocaine, disrupt circadian metabolic profiles in the liver, which is exacerbated by loss of D2R signaling in MSNs. These results uncover a strict communication between neurons/brain areas and liver metabolism as well as the association between substance use and systemic deficits.

Nature biomedical engineering

评语： 

除了药物治疗和手术治疗外，通过生物医学工程或各种物理手段实现的神经调控策略已经被广泛用于诸多疾病的临床治疗，甚至包括免疫疾病和代谢疾病等传统上被认为是非神经系统的疾病，如类风湿关节炎和肠易激综合征等。但运用如经皮磁刺激、经颅磁刺激以及深部脑刺激等物理手段治疗疾病，存在一定的局限性，如刺激深度不够，不能够准确到达目标靶点，或者需要有创植入设备，有一定风险。本文提供的外周神经超声刺激方式无创安全，也可以避免药物的副作用。

关键词： 

peripheral focused ultrasound stimulation（pFUS）；Glucose homoeostasis；hepathoportal nerve plexus；PVN；NPY

文章链接 ： 

https://www.nature.com/articles/s41551-022-00870-w

Abstract

Peripheral neurons that sense glucose relay signals of glucose availability to integrative clusters of neurons in the brain. However, the roles of such signalling pathways in the maintenance of glucose homoeostasis and their contribution to disease are unknown. Here we show that the selective activation of the nerve plexus of the hepatic portal system via peripheral focused ultrasound stimulation (pFUS) improves glucose homoeostasis in mice and rats with insulin-resistant diabetes and in swine subject to hyperinsulinemic-euglycaemic clamps. pFUS modulated the activity of sensory projections to the hypothalamus, altered the concentrations of metabolism-regulating neurotransmitters, and enhanced glucose tolerance and utilization in the three species, whereas physical transection or chemical blocking of the liver–brain nerve pathway abolished the effect of pFUS on glucose tolerance. Longitudinal multi-omic profiling of metabolic tissues from the treated animals confirmed pFUS-induced modifications of key metabolic functions in liver, pancreas, muscle, adipose, kidney and intestinal tissues. Non-invasive ultrasound activation of afferent autonomic nerves may represent a non-pharmacologic therapy for the restoration of glucose homoeostasis in type-2 diabetes and other metabolic diseases.

Cell Metabolism

中枢在调控血糖过高和胰岛素分泌中起重要作用，这个共识在代谢领域已存在百年以上。以往的研究通过病毒示踪解析了中枢与胰腺之间的神经投射，然而大脑和胰岛β细胞之间的解剖和功能连接还需要进一步阐明。

在这篇文章中，作者利用伪狂犬病毒追踪下丘脑室旁核（paraventricular hypothalamic nucleus，PVN）的OXT神经元（oxytocin neurons，催产素神经元）通过交感神经向胰腺发出功能投射。通过光遗传学，发现激活PVN^OXT神经元会迅速抑制胰岛β细胞分泌胰岛素，并造成血糖升高；而光遗传学抑制则产生相反的效果。进一步研究发现PVN^OXT的活性会由于葡萄糖缺乏而被激活。综上所述，本文揭示了通过多级投射调控胰岛β细胞分泌胰岛素的中枢脑区，拓展了我们对外周器官与中枢神经相互作用及及其机制的认知。

评语： 

领域内很早就发现自主神经系统参与代谢器官功能的调控，但是对其上游中枢的脑区机制和细胞类型机制并不明确。本研究揭示了摄食和代谢关键脑区PVN通过多级神经投射，调控胰腺释放胰岛素的功能，并解析出其精细的神经元类型机制。此外既往研究表明PVN通过整合下丘脑其他亚区的信号，向肝脏发出多级神经投射，调控其代谢功能，本研究丰富了我们对于PVN与除肝脏外的代谢器官之间功能投射的认识。

关键词： 

paraventricular hypothalamic nucleus（PVN）；oxytocin neurons（OXT）；pancreatic b cells；insulin secretion

文章链接： 

https://doi.org/10.1016/j.cmet.2021.12.020

Abstract

The central nervous system has long been thought to regulate insulin secretion, an essential process in the maintenance of blood glucose levels. However, the anatomical and functional connections between the brain and insulin-producing pancreatic β cells remain undefined. Here, we describe a functional transneuronal circuit connecting the hypothalamus to β cells in mice. This circuit originates from a subpopulation of oxytocin neurons in the paraventricular hypothalamic nucleus (PVN^OXT), and it reaches the islets of the endocrine pancreas via the sympathetic autonomic branch to innervate β cells. Stimulation of PVN^OXT neurons rapidly suppresses insulin secretion and causes hyperglycemia. Conversely, silencing of these neurons elevates insulin levels by dysregulating neuronal signaling and secretory pathways in β cells and induces hypoglycemia. PVN^OXT neuronal activity is triggered by glucoprivation. Our findings reveal that a subset of PVN^OXT neurons form functional multisynaptic circuits with β cells in mice to regulate insulin secretion, and their function is necessary for the β cell response to hypoglycemia.