下丘脑长型催乳素受体(PRLR-L)对机体胰岛素敏感性的调控作用及分子机制

In recent years, there has been a global epidemic trend for type 2 diabetes mellitus (T2DM). The fundamental character of T2DM is insulin resistance (IR).Hypothalamus is the metabolic regulatory center which plays an important role in the regulation of insulin sensitivity. Prolactin receptor (PRLR) is a multi-functional hormonal receptor which is highly expressed in the hypothalamus. The long isoform of PRLR (PRLR-L) is the predominant form expressing in the hypothalamus. Although PRLR has been reported in numerous physiological functions, the role of hypothalamic PRLR in the regulation of peripheral glucose homeostasis and insulin sensitivity remains largely unknown. The preliminary results of the applicant show that inhibiting hypothalamic PRLR-L greatly decreases insulin sensitivity, whereas overexpression of PRLR-L in hypothalamus has the opposite effect. Therefore, we suspect that hypothalamic PRLR-L plays an important role in the regulation of peripheral insulin sensitivity. . The current project will apply the technique of intrathirdventrical injection and primary hypothalamic neuron culture, in combination of adenovirus gene expression system, immunohistochemistry, glucose tolerance test(GTT), insulin tolerance test(ITT) and in vivo insulin signaling test to explore the role and mechanism of hypothalamic PRLR-L in the regulation of peripheral insulin sensitivity. The achievements of the current project will help to identify the novel function of central PRLR-L, deepen the understanding for the hypothalamic control of insulin sensitivity, and provide important theoretical evidence for exploring the pathological mechanism of T2DM and other related metabolic disease.

目前2型糖尿病在全球呈高度流行趋势，其核心病理特征是胰岛素抵抗，而代谢调节中枢下丘脑对机体胰岛素敏感性有重要调控作用。催乳素受体(PRLR)是一种在下丘脑高表达的多功能激素受体，其中长型催乳素受体(PRLR-L)是下丘脑的主要功能亚型。目前，下丘脑PRLR-L在外周胰岛素敏感性调控中的作用尚无报道。申请人前期结果表明，下丘脑PRLR-L缺失会诱导显著的胰岛素抵抗，过表达PRLR-L则增加胰岛素敏感性，故推测PRLR-L是维持机体胰岛素敏感性的重要调节因子。本项目将利用小鼠第三脑室注射和下丘脑神经元原代培养等技术，结合腺病毒表达系统、免疫组化、GTT、ITT、组织胰岛素信号通路分析等方法，对下丘脑PRLR-L调控胰岛素敏感性的作用和机制进行研究。本项目的研究成果将解析下丘脑PRLR-L的新功能，丰富下丘脑调控胰岛素敏感性的理论知识，为研究2型糖尿病及相关代谢性疾病的发病机制提供重要理论依据。

目前2型糖尿病在全球呈高度流行趋势，其核心病理特征是胰岛素抵抗，而代谢调节中枢下丘脑对机体胰岛素敏感性有重要调控作用。催乳素受体(PRLR)是一种在下丘脑高表达的多功能激素受体，其中长型催乳素受体(PRLR-L)是下丘脑的主要功能亚型。本项目开展前，下丘脑PRLR-L在外周胰岛素敏感性调控中的作用尚无报道。本项目采用第三脑室注射腺病毒、肝迷走神经切除术等技术手段，利用胰岛素抵抗db/db小鼠模型，在多个层次深入研究了下丘脑PRLR对外周胰岛素敏感性及糖代谢稳态的调控作用及机制。申请人研究发现，下丘脑PRLR缺失会诱导显著的胰岛素抵抗，过表达PRLR则增加野生型小鼠及db/db小鼠的胰岛素敏感性；PRLR增加胰岛素敏感性的功能主要依赖于下丘脑的STAT5B的磷酸化蛋白水平（p-STAT5），并且通过肝脏迷走神经将信号传导至外周组织；此外，我们还发现，抗精神病药物氯氮平clozapine引起的胰岛素抵抗可被中枢的PRLR过表达所逆转。这些结果首次证明了中枢催乳素受体调控机体胰岛素敏感性的作用及其分子机制,为研究2型糖尿病的发病机制和治疗药物靶点提供了重要理论依据。