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Cellular functional roles of celastrol on mitochondrial dysfunction-induced insulin resistance

There are compelling evidence showing that mitochondrial dysfunction and low-grade chronic inflammation in several peripheral tissues may attribute to the central pathophysiological mechanism of insulin resistance and type 2 diabetes. Celastrol, a pentacyclic-triterpene, is an established anti-infla...

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Main Author: Abu Bakar, Mohamad Hafizi
Format: Thesis
Language:English
Published: 2015
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TP Chemical technology
Online Access:http://eprints.utm.my/id/eprint/77717/1/MohamadHafiziAbuPFChE2015.pdf
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spelling my.utm.777172018-06-29T21:29:56Z http://eprints.utm.my/id/eprint/77717/ Cellular functional roles of celastrol on mitochondrial dysfunction-induced insulin resistance Abu Bakar, Mohamad Hafizi TP Chemical technology There are compelling evidence showing that mitochondrial dysfunction and low-grade chronic inflammation in several peripheral tissues may attribute to the central pathophysiological mechanism of insulin resistance and type 2 diabetes. Celastrol, a pentacyclic-triterpene, is an established anti-inflammatory agent from the root of Tripterygium wilfordii that has been used for centuries as medicament to treat numerous inflammatory diseases. As its therapeutic treatment is increasingly being recognized, the present study sought to investigate the functional roles of celastrol upon mitochondrial dysfunction and insulin resistance induced by mitochondrial respiratory inhibitors in insulin responsive cells. The glucose uptake activity, mitochondrial functions, lipolysis, intracellular lipid accumulation and a number of signaling pathways were investigated using cell-based assays and western blot analyses. The optimum doses of celastrol in improving insulin-stimulated glucose uptake of mitochondrial inhibitors-treated 3T3-L1 adipocytes, human skeletal muscle and C3A human liver cells were 5, 15 and 30 nM, respectively. Celastrol treatment for 48 hours improved the mitochondrial activities and decreased the mitochondrial superoxide productions. The integrity of mitochondrial dynamics was restored via substantial changes in mitochondrial fusion and fission. Furthermore, celastrol prevented the amplified level of cellular oxidative damages where the production of proinflammatory cytokines in cultured cells was greatly down-regulated. The release of free fatty acids and glycerol from conditioned media of adipocytes and hepatocytes were reduced after celastrol treatment. The relative amount of intracellular lipid accumulation was decreased in celastrol-treated cells with mitochondrial dysfunction. Importantly, celastrol enhanced the phosphorylation of amino acid residues of insulin receptor substrate 1 (IRS1), serine/threonine kinase (Akt/PKB) and Akt substrate 160 (AS160) proteins in insulin signaling pathways with amplified expression of 5' adenosine monophosphate-activated protein kinase (AMPK) protein in human myotubes and hepatocytes. The metabolic effects of celastrol were also accompanied with the attenuation of nuclear factor-kappa B (NF-κB) and diminished activation of the protein kinase C (PKC) isoforms in insulin resistant cells. The protein expression of glucose transporter 4 (GLUT4) was normalized by celastrol in adipocytes and human myotubes while reduced GLUT2 protein expression was observed in hepatocytes, signifying its ameliorative properties in enhancing insulin sensitivity of these in vitro disease models. Collectively, these results unequivocally suggested that celastrol may be advocated for use as a potential therapeutic molecule to protect against mitochondrial dysfunction and inflammation in the development of insulin resistance and type 2 diabetes. 2015-11 Thesis NonPeerReviewed application/pdf en http://eprints.utm.my/id/eprint/77717/1/MohamadHafiziAbuPFChE2015.pdf Abu Bakar, Mohamad Hafizi (2015) Cellular functional roles of celastrol on mitochondrial dysfunction-induced insulin resistance. PhD thesis, Universiti Teknologi Malaysia, Faculty of Chemical and Energy Engineering. http://dms.library.utm.my:8080/vital/access/manager/Repository/vital:95345
institution Universiti Teknologi Malaysia
building UTM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Teknologi Malaysia
content_source UTM Institutional Repository
url_provider http://eprints.utm.my/
language English
topic TP Chemical technology
spellingShingle TP Chemical technology
Abu Bakar, Mohamad Hafizi
Cellular functional roles of celastrol on mitochondrial dysfunction-induced insulin resistance
description There are compelling evidence showing that mitochondrial dysfunction and low-grade chronic inflammation in several peripheral tissues may attribute to the central pathophysiological mechanism of insulin resistance and type 2 diabetes. Celastrol, a pentacyclic-triterpene, is an established anti-inflammatory agent from the root of Tripterygium wilfordii that has been used for centuries as medicament to treat numerous inflammatory diseases. As its therapeutic treatment is increasingly being recognized, the present study sought to investigate the functional roles of celastrol upon mitochondrial dysfunction and insulin resistance induced by mitochondrial respiratory inhibitors in insulin responsive cells. The glucose uptake activity, mitochondrial functions, lipolysis, intracellular lipid accumulation and a number of signaling pathways were investigated using cell-based assays and western blot analyses. The optimum doses of celastrol in improving insulin-stimulated glucose uptake of mitochondrial inhibitors-treated 3T3-L1 adipocytes, human skeletal muscle and C3A human liver cells were 5, 15 and 30 nM, respectively. Celastrol treatment for 48 hours improved the mitochondrial activities and decreased the mitochondrial superoxide productions. The integrity of mitochondrial dynamics was restored via substantial changes in mitochondrial fusion and fission. Furthermore, celastrol prevented the amplified level of cellular oxidative damages where the production of proinflammatory cytokines in cultured cells was greatly down-regulated. The release of free fatty acids and glycerol from conditioned media of adipocytes and hepatocytes were reduced after celastrol treatment. The relative amount of intracellular lipid accumulation was decreased in celastrol-treated cells with mitochondrial dysfunction. Importantly, celastrol enhanced the phosphorylation of amino acid residues of insulin receptor substrate 1 (IRS1), serine/threonine kinase (Akt/PKB) and Akt substrate 160 (AS160) proteins in insulin signaling pathways with amplified expression of 5' adenosine monophosphate-activated protein kinase (AMPK) protein in human myotubes and hepatocytes. The metabolic effects of celastrol were also accompanied with the attenuation of nuclear factor-kappa B (NF-κB) and diminished activation of the protein kinase C (PKC) isoforms in insulin resistant cells. The protein expression of glucose transporter 4 (GLUT4) was normalized by celastrol in adipocytes and human myotubes while reduced GLUT2 protein expression was observed in hepatocytes, signifying its ameliorative properties in enhancing insulin sensitivity of these in vitro disease models. Collectively, these results unequivocally suggested that celastrol may be advocated for use as a potential therapeutic molecule to protect against mitochondrial dysfunction and inflammation in the development of insulin resistance and type 2 diabetes.
format Thesis
author Abu Bakar, Mohamad Hafizi
author_facet Abu Bakar, Mohamad Hafizi
author_sort Abu Bakar, Mohamad Hafizi
title Cellular functional roles of celastrol on mitochondrial dysfunction-induced insulin resistance
title_short Cellular functional roles of celastrol on mitochondrial dysfunction-induced insulin resistance
title_full Cellular functional roles of celastrol on mitochondrial dysfunction-induced insulin resistance
title_fullStr Cellular functional roles of celastrol on mitochondrial dysfunction-induced insulin resistance
title_full_unstemmed Cellular functional roles of celastrol on mitochondrial dysfunction-induced insulin resistance
title_sort cellular functional roles of celastrol on mitochondrial dysfunction-induced insulin resistance
publishDate 2015
url http://eprints.utm.my/id/eprint/77717/1/MohamadHafiziAbuPFChE2015.pdf
http://eprints.utm.my/id/eprint/77717/
http://dms.library.utm.my:8080/vital/access/manager/Repository/vital:95345
_version_ 1643657613370458112
score 13.211869

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