Biomembrane Lab, Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tamilnadu, India.
Front Endocrinol (Lausanne). 2022 Jul 22;13:927576. doi: 10.3389/fendo.2022.927576. eCollection 2022.
Obesity 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.
The 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.
The 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.
We 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.
The pharmacological mechanism of action in this study shows the ten therapeutic targets of melatonin in LR-induced obesity.
肥胖是一种医学问题，会增加其他代谢紊乱的风险，如糖尿病、心脏问题、关节炎等。瘦素是一种由脂肪组织分泌的激素，负责食物摄入、能量消耗等，而瘦素抵抗是肥胖的重要原因之一。不良的饮食习惯导致瘦素过度分泌，下丘脑瘦素信号受损，导致 LR。褪黑素是一种睡眠激素，具有抗氧化和抗炎作用。褪黑素可以通过调节其对瘦素抵抗诱导肥胖的靶点来减轻肥胖的并发症。
本研究旨在通过系统药理学方法进行分子途径和网络分析，确定褪黑素治疗瘦素抵抗诱导肥胖的潜在治疗机制。
使用生物信息学方法寻找褪黑素治疗瘦素抵抗诱导肥胖的治疗靶点。它包括使用公共数据库、GO 和 KEGG 途径富集使用 R 语言中的 'ClusterProfiler' 识别基因，使用 Cytoscape 进行网络分析，以及使用 Autodock 进行分子对接。
我们从 254 个褪黑素总靶点和 212 个 LR 肥胖共同靶点中，使用数据筛选方法获得了褪黑素和 LR 诱导肥胖的共同前 33 个潜在治疗靶点。它们涉及与睡眠和肥胖相关的生物学过程，包括细胞对外界刺激、化学应激和自噬的反应。在总共 180 个富集途径中，我们选择了前 10 个途径进行进一步分析，包括脂质和动脉粥样硬化、内分泌和糖尿病并发症中的 AGE-RAGE 信号通路。前 10 个途径与共同的 33 个基因相互作用，形成了两个功能模块。使用 Cytoscape 网络分析，通过 CytoHubba 插件的 MCC 算法识别出前 10 个 hub 基因（TP53、AKT1、MAPK3、PTGS2、TNF、IL6、MAPK1、ERBB2、IL1B、MTOR）。从广泛的途径类别来看，褪黑素可以通过调节主要的六大类来降低 LR 诱导的肥胖风险。它包括信号转导、内分泌系统、内分泌和代谢疾病、环境适应、耐药抗肿瘤和心血管疾病。
本研究的药理作用机制表明，褪黑素在 LR 诱导的肥胖中有 10 个治疗靶点。
