He Yirui, Zhang Cheng, Wu Shaobo, Li Ke, Zhang Siliang, Tian Mingyuan, Chen Chen, Liu Dongfang, Yang Gangyi, Li Ling, Yang Mengliu
Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Metabolism. 2025 Jan;162:156046. doi: 10.1016/j.metabol.2024.156046. Epub 2024 Oct 9.
BACKGROUND & AIMS: Nucleobindin-2 (NUCB2)/nesfatin-1, a signal with recognized anorexigenic and insulin-sensitizing properties in peripheral tissues, is expressed within the hypothalamus. However, the potential involvement of central nesfatin-1 signaling in the pathophysiology of hepatic steatosis remains unknown. This study aimed to determine whether and how central NUCB2/nesfatin-1 plays a role in liver steatosis.
We generated Nucb2 knockout (Nucb2) rats and administered continuous intracerebroventricular (ICV) nesfatin-1 infusion, while observing its effect on liver steatosis. The molecular mechanism of action of nesfatin-1 was elucidated via proteomics, phosphoproteomics and molecular biology methods.
Herein, we present compelling evidence indicating diminished NUCB2 expression in the hypothalamus of obese rodents. We demonstrated that chronic ICV infusion of nesfatin-1 mitigated both diet-induced obesity and liver steatosis in high-fat diet (HFD)-fed Nucb2 rats by regulating hypothalamic endoplasmic reticulum (ER) stress and Akt phosphorylation. Furthermore, we revealed that the increase in hypothalamic insulin resistance (IR) and ER stress induced by tunicamycin infusion or Ero1α overexpression exacerbated hepatic steatosis and offset the favorable influence of central nesfatin-1 on hepatic steatosis. The metabolic action of central nesfatin-1 is contingent upon vagal nerve transmission to the liver. Mechanistically, nesfatin-1 impedes ER stress and interacts with Ero1α to repress its Ser106 phosphorylation. This leads to the enhancement of Akt activity in the hypothalamus, culminating in the inhibition of hepatic lipogenesis.
These findings underscore the importance of hypothalamic NUCB2/nesfatin-1 as a key mediator in the top-down neural mechanism that combats diet-induced liver steatosis.
核结合蛋白2（NUCB2）/nesfatin-1是一种在外周组织中具有公认的厌食和胰岛素增敏特性的信号分子，在下丘脑中也有表达。然而，中枢nesfatin-1信号在肝脂肪变性病理生理学中的潜在作用仍不清楚。本研究旨在确定中枢NUCB2/nesfatin-1是否以及如何在肝脏脂肪变性中发挥作用。
我们构建了Nucb2基因敲除（Nucb2）大鼠，并持续进行脑室内（ICV）nesfatin-1输注，同时观察其对肝脏脂肪变性的影响。通过蛋白质组学、磷酸蛋白质组学和分子生物学方法阐明nesfatin-1的分子作用机制。
在此，我们提供了令人信服的证据，表明肥胖啮齿动物下丘脑的NUCB2表达降低。我们证明，在高脂饮食（HFD）喂养的Nucb2大鼠中，长期ICV输注nesfatin-1可通过调节下丘脑内质网（ER）应激和Akt磷酸化减轻饮食诱导的肥胖和肝脏脂肪变性。此外，我们发现衣霉素输注或Ero1α过表达诱导的下丘脑胰岛素抵抗（IR）和ER应激增加会加剧肝脏脂肪变性，并抵消中枢nesfatin-1对肝脏脂肪变性的有利影响。中枢nesfatin-1的代谢作用取决于迷走神经向肝脏的传递。机制上，nesfatin-1可抑制ER应激，并与Ero1α相互作用以抑制其Ser106磷酸化。这导致下丘脑Akt活性增强，最终抑制肝脏脂肪生成。
这些发现强调了下丘脑NUCB2/nesfatin-1作为对抗饮食诱导的肝脏脂肪变性的自上而下神经机制中的关键介质的重要性。
