Table_3_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.

研究背景
肥胖是一类临床常见医学问题，可显著提升糖尿病、心脏疾病、关节炎等其他代谢紊乱类疾病的发病风险。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）是肥胖发生的核心诱因之一。不良饮食习惯引发的瘦素过度分泌，以及下丘脑瘦素信号通路受损，均可诱发瘦素抵抗。褪黑素（Melatonin）作为睡眠相关激素，同时具备抗氧化与抗炎特性。其可通过靶向调控瘦素抵抗型肥胖的相关靶点，缓解肥胖相关并发症。

研究目的
本研究旨在采用系统药理学方法开展分子通路与网络分析，阐明褪黑素针对瘦素抵抗型肥胖的潜在治疗机制。

研究方法
本研究通过生物信息学方法筛选褪黑素治疗瘦素抵抗型肥胖的潜在治疗靶点，具体包括：依托公共数据库进行靶基因鉴定；采用R语言中的"ClusterProfiler"工具开展基因本体（Gene Ontology, GO）富集分析与京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）通路富集分析；通过Cytoscape软件进行网络分析；以及采用Autodock完成分子对接。

研究结果
本研究通过数据筛选策略，从254个褪黑素靶基因与212个瘦素抵抗型肥胖相关靶基因中，筛选得到二者共有的33个潜在治疗核心靶点。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、化学应激响应以及自噬调控等。在共计180条富集得到的通路中，选取前10条关键通路开展后续分析，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晚期糖基化终末产物-晚期糖基化终末产物受体（AGE-RAGE）信号通路等。上述10条关键通路与33个共有靶点存在相互作用，可构建出两个功能模块。通过Cytoscape的CytoHubba插件的最大团中心性（Maximal Clique Centrality, 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）。从通路分类维度来看，褪黑素可通过调控六大类主要通路以降低瘦素抵抗型肥胖的发病风险，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相关通路。

研究结论
本研究阐明的药理学作用机制，明确了褪黑素针对瘦素抵抗型肥胖的10个治疗靶点。