DataSheet_1_Therapeutic Target Analysis and Molecular Mechanism of Melatonin - Treated Leptin Resistance Induced Obesity: A Systematic Study of Network Pharmacology.docx

BackgroundObesity is a medical problem with an increased risk for other metabolic disorders like diabetes, heart problem, arthritis, etc. Leptin is an adipose tissue-derived hormone responsible for food intake, energy expenditure, etc., and leptin resistance is one of the significant causes of obesity. Excess leptin secretion by poor diet habits and impaired hypothalamic leptin signaling leads to LR. Melatonin a sleep hormone; also possess antioxidant and anti-inflammatory properties. The melatonin can attenuate the complications of obesity by regulating its targets towards LR induced obesity.AimThe aim of this study includes molecular pathway and network analysis by using a systems pharmacology approach to identify a potential therapeutic mechanism of melatonin on leptin resistance-induced obesity.MethodsThe bioinformatic methods are used to find therapeutic targets of melatonin in the treatment of leptin resistance-induced obesity. It includes target gene identification using public databases, Gene ontology, and KEGG pathway enrichment by ‘ClusterProfiler’ using the R language, network analysis by Cytoscape, and molecular Docking by Autodock.ResultsWe obtained the common top 33 potential therapeutic targets of melatonin and LR-induced obesity from the total melatonin targets 254 and common LR obesity targets 212 using the data screening method. They are involved in biological processes related to sleep and obesity, including the cellular response to external stimulus, chemical stress, and autophagy. From a total of 180 enriched pathways, we took the top ten pathways for further analysis, including lipid and atherosclerosis, endocrine, and AGE-RAGE signaling pathway in diabetic complications. The top 10 pathways interacted with the common 33 genes and created two functional modules. Using Cytoscape network analysis, the top ten hub genes (TP53, AKT1, MAPK3, PTGS2, TNF, IL6, MAPK1, ERBB2, IL1B, MTOR) were identified by the MCC algorithm of the CytoHubba plugin. From a wide range of pathway classes, melatonin can reduce LR-induced obesity risks by regulating the major six classes. It includes signal transduction, endocrine system, endocrine and metabolic disease, environmental adaptation, drug resistance antineoplastic, and cardiovascular disease.ConclusionThe pharmacological mechanism of action in this study shows the ten therapeutic targets of melatonin in LR-induced obesity.

背景：肥胖症是一种增加患其他代谢性疾病风险的医学问题，如糖尿病、心脏病、关节炎等。瘦素是一种由脂肪组织分泌的激素，负责调节食物摄入、能量消耗等，而瘦素抵抗是肥胖的重要成因之一。不良饮食习惯和下丘脑瘦素信号传导障碍导致的瘦素分泌过剩，会引发瘦素抵抗（LR）。褪黑素，一种睡眠激素，同时具备抗氧化和抗炎特性。褪黑素可以通过调节其靶点，减轻由瘦素抵抗诱导的肥胖并发症。研究目标：本研究的目的是通过系统药理学方法，利用分子通路和网络分析，识别褪黑素在瘦素抵抗诱导的肥胖中的潜在治疗机制。方法：本研究采用生物信息学方法寻找褪黑素治疗瘦素抵抗诱导的肥胖的靶点，包括利用公共数据库进行目标基因识别、利用R语言中的‘ClusterProfiler’进行基因本体和KEGG通路富集分析、使用Cytoscape进行网络分析以及使用Autodock进行分子对接。结果：通过数据筛选方法，我们从褪黑素的总靶点254个和瘦素抵抗肥胖的共有靶点212个中，获得了褪黑素的33个常见潜在治疗靶点。这些靶点涉及与睡眠和肥胖相关的生物过程，包括细胞对外部刺激、化学应激和自噬的响应。在总共180个富集通路中，我们选取了前十个通路进行进一步分析，包括脂质和动脉粥样硬化、内分泌以及糖尿病并发症中的AGE-RAGE信号通路。这十个通路与共同的33个基因相互作用，形成了两个功能模块。通过Cytoscape网络分析，利用CytoHubba插件的MCC算法确定了前十个枢纽基因（TP53、AKT1、MAPK3、PTGS2、TNF、IL6、MAPK1、ERBB2、IL1B、MTOR）。褪黑素可以通过调节主要的六个类别来降低瘦素抵抗诱导的肥胖风险，这包括信号传导、内分泌系统、内分泌和代谢疾病、环境适应、耐药性抗肿瘤和心血管疾病。结论：本研究揭示了褪黑素在瘦素抵抗诱导的肥胖中的十个治疗靶点。