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Elucidating type 2 diabetes mellitus risk factor by promoting lipid metabolism with gymnemagenin: An in vitro and in silico approach
Introduction: Adipose tissue functions as a key endocrine organ which releases multiple bioactive substances and regulate obesity-linked complications. Dysregulation of adipocyte differentiation, triglyceride metabolism, adipokines production and lipid transport contributes to impaired lipid metabol...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9792475/ https://www.ncbi.nlm.nih.gov/pubmed/36582536 http://dx.doi.org/10.3389/fphar.2022.1074342 |
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author | DasNandy, Anusree Patil, Vishal S. Hegde, Harsha V. Harish, Darasaguppe R. Roy, Subarna |
author_facet | DasNandy, Anusree Patil, Vishal S. Hegde, Harsha V. Harish, Darasaguppe R. Roy, Subarna |
author_sort | DasNandy, Anusree |
collection | PubMed |
description | Introduction: Adipose tissue functions as a key endocrine organ which releases multiple bioactive substances and regulate obesity-linked complications. Dysregulation of adipocyte differentiation, triglyceride metabolism, adipokines production and lipid transport contributes to impaired lipid metabolism resulting in obesity, insulin resistance and type 2 diabetes. Gymnema sylvestre plant is frequently used in Ayurveda for treatment of diabetes and obesity. Gymnemagenin is a major bioactive compound of Gymnema sylvestre. The present study was undertaken to elucidate the role of gymnemagenin in lipid metabolism by in vitro and computational approaches. Methods: A panel of twelve genes viz., Fasn, Lipe, Lpl, Pparg, Plin2, Cidea, Scd1, Adipoq, Lep, Ccl2, Fabp4, and Slc2a4, essential in lipid metabolism were selected and gene expression pattern and triglyceride content were checked in adipocytes (3T3L1 cells) with/without treatment of gymnemagenin by Real time PCR and colorimetric estimation, respectively. Mode of action of gymnemagenin on Pparg and Fabp4 was accomplished by computational studies. Gene set enrichment and network pharmacology were performed by STRING and Cytoscape. Molecular docking was performed by AutoDock vina by POAP pipeline. Molecular dynamics, MM-PBSA were done by Gromacs tool. Results: In vitro study showed that gymnemagenin improved triglyceride metabolism by up regulating the expression of lipase genes viz., Lipe and Lpl which hydrolyse triglyceride. Gymnemagenin also up regulated the expression of anti-inflammatory gene Adipoq. Importantly, gymnemagenin treatment up regulated the expression of Pparg gene and the downstream target genes (Plin2, Cidea, and Scd1) which are associated with adipogenesis. However, gymnemagenin has no effect on expression of Fabp4, codes for a lipid transport protein. In silico study revealed that gymnemagenin targeted 12 genes were modulating 6 molecular pathways involved in diabetes and obesity. Molecular docking and dynamics revealed that gymnemagenin stably bind to active site residue of Pparg and failed to bind to Fabp4 active site compared to its standard molecules throughout 100 ns MD production run. Gymnemagenin scored binding free energy of −177.94 and −25.406 kJ/mol with Pparg and Fabp4, respectively. Conclusion: Gymnemagenin improved lipid metabolism by increasing triglyceride hydrolysis (lipolysis), up regulating the crucial gene of adipogenesis and increasing the expression of anti-inflammatory adipokine proving its therapeutic importance as anti-obesity and anti-diabetic phytocompound. |
format | Online Article Text |
id | pubmed-9792475 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97924752022-12-28 Elucidating type 2 diabetes mellitus risk factor by promoting lipid metabolism with gymnemagenin: An in vitro and in silico approach DasNandy, Anusree Patil, Vishal S. Hegde, Harsha V. Harish, Darasaguppe R. Roy, Subarna Front Pharmacol Pharmacology Introduction: Adipose tissue functions as a key endocrine organ which releases multiple bioactive substances and regulate obesity-linked complications. Dysregulation of adipocyte differentiation, triglyceride metabolism, adipokines production and lipid transport contributes to impaired lipid metabolism resulting in obesity, insulin resistance and type 2 diabetes. Gymnema sylvestre plant is frequently used in Ayurveda for treatment of diabetes and obesity. Gymnemagenin is a major bioactive compound of Gymnema sylvestre. The present study was undertaken to elucidate the role of gymnemagenin in lipid metabolism by in vitro and computational approaches. Methods: A panel of twelve genes viz., Fasn, Lipe, Lpl, Pparg, Plin2, Cidea, Scd1, Adipoq, Lep, Ccl2, Fabp4, and Slc2a4, essential in lipid metabolism were selected and gene expression pattern and triglyceride content were checked in adipocytes (3T3L1 cells) with/without treatment of gymnemagenin by Real time PCR and colorimetric estimation, respectively. Mode of action of gymnemagenin on Pparg and Fabp4 was accomplished by computational studies. Gene set enrichment and network pharmacology were performed by STRING and Cytoscape. Molecular docking was performed by AutoDock vina by POAP pipeline. Molecular dynamics, MM-PBSA were done by Gromacs tool. Results: In vitro study showed that gymnemagenin improved triglyceride metabolism by up regulating the expression of lipase genes viz., Lipe and Lpl which hydrolyse triglyceride. Gymnemagenin also up regulated the expression of anti-inflammatory gene Adipoq. Importantly, gymnemagenin treatment up regulated the expression of Pparg gene and the downstream target genes (Plin2, Cidea, and Scd1) which are associated with adipogenesis. However, gymnemagenin has no effect on expression of Fabp4, codes for a lipid transport protein. In silico study revealed that gymnemagenin targeted 12 genes were modulating 6 molecular pathways involved in diabetes and obesity. Molecular docking and dynamics revealed that gymnemagenin stably bind to active site residue of Pparg and failed to bind to Fabp4 active site compared to its standard molecules throughout 100 ns MD production run. Gymnemagenin scored binding free energy of −177.94 and −25.406 kJ/mol with Pparg and Fabp4, respectively. Conclusion: Gymnemagenin improved lipid metabolism by increasing triglyceride hydrolysis (lipolysis), up regulating the crucial gene of adipogenesis and increasing the expression of anti-inflammatory adipokine proving its therapeutic importance as anti-obesity and anti-diabetic phytocompound. Frontiers Media S.A. 2022-12-13 /pmc/articles/PMC9792475/ /pubmed/36582536 http://dx.doi.org/10.3389/fphar.2022.1074342 Text en Copyright © 2022 DasNandy, Patil, Hegde, Harish and Roy. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology DasNandy, Anusree Patil, Vishal S. Hegde, Harsha V. Harish, Darasaguppe R. Roy, Subarna Elucidating type 2 diabetes mellitus risk factor by promoting lipid metabolism with gymnemagenin: An in vitro and in silico approach |
title | Elucidating type 2 diabetes mellitus risk factor by promoting lipid metabolism with gymnemagenin: An in vitro and in silico approach |
title_full | Elucidating type 2 diabetes mellitus risk factor by promoting lipid metabolism with gymnemagenin: An in vitro and in silico approach |
title_fullStr | Elucidating type 2 diabetes mellitus risk factor by promoting lipid metabolism with gymnemagenin: An in vitro and in silico approach |
title_full_unstemmed | Elucidating type 2 diabetes mellitus risk factor by promoting lipid metabolism with gymnemagenin: An in vitro and in silico approach |
title_short | Elucidating type 2 diabetes mellitus risk factor by promoting lipid metabolism with gymnemagenin: An in vitro and in silico approach |
title_sort | elucidating type 2 diabetes mellitus risk factor by promoting lipid metabolism with gymnemagenin: an in vitro and in silico approach |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9792475/ https://www.ncbi.nlm.nih.gov/pubmed/36582536 http://dx.doi.org/10.3389/fphar.2022.1074342 |
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