Table_5_Therapeutic Target Analysis and Molecular Mechanism of Melatonin - Treated Leptin Resistance Induced Obesity: A Systematic Study of Network Pharmacology.xlsx

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 肥胖是一类可提升糖尿病、心脏疾病、关节炎等多种代谢紊乱病症发病风险的医学问题。瘦素（leptin）是一种由脂肪组织分泌的激素，参与调控食物摄入与能量消耗等生理过程，而瘦素抵抗（leptin resistance, LR）是诱发肥胖的重要原因之一。不良饮食习惯导致的瘦素过度分泌，以及下丘脑瘦素信号通路受损，均可引发瘦素抵抗。褪黑素（melatonin）作为睡眠激素，同时具备抗氧化与抗炎特性，可通过靶向调控瘦素抵抗诱导肥胖的相关通路，缓解肥胖相关并发症。
目的 本研究采用系统药理学（systems pharmacology）方法开展分子通路与网络分析，以明确褪黑素治疗瘦素抵抗诱导肥胖的潜在作用机制。
方法 本研究通过生物信息学方法筛选褪黑素用于治疗瘦素抵抗诱导肥胖的潜在治疗靶点。具体内容包括：依托公共数据库进行靶基因鉴定；采用R语言中的'ClusterProfiler'包开展基因本体（Gene Ontology, GO）与京都基因与基因组百科全书通路（KEGG pathway）富集分析；通过Cytoscape软件进行网络分析；使用AutoDock开展分子对接（molecular docking）。
结果 本研究从254个褪黑素靶点与212个瘦素抵抗肥胖相关靶点中，经数据筛选得到二者共有的33个潜在治疗靶点。这些靶点参与睡眠与肥胖相关的生物学过程，包括细胞对外界刺激的应答、化学应激应答以及自噬过程。从共计180条富集通路中，筛选出前10条用于后续分析，涵盖脂质与动脉粥样硬化、内分泌系统以及糖尿病并发症中的AGE-RAGE信号通路等。上述10条富集通路与33个共有靶点基因存在相互作用，并构建出2个功能模块。通过Cytoscape的CytoHubba插件的马修斯相关系数（Matthews Correlation Coefficient, MCC）算法，筛选得到排名前十的核心靶点基因：TP53、AKT1、MAPK3、PTGS2、TNF、IL6、MAPK1、ERBB2、IL1B、MTOR。褪黑素可通过调控六大类通路降低瘦素抵抗诱导肥胖的发病风险，涵盖信号转导、内分泌系统、内分泌与代谢性疾病、环境适应、抗肿瘤耐药以及心血管疾病。
结论 本研究揭示的褪黑素药理作用机制，明确了其治疗瘦素抵抗诱导肥胖的10个治疗靶点。