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Int. J. Mol. Sci. 2014, 15(12), 22227-22257; doi:10.3390/ijms151222227

Amelioration of Mitochondrial Dysfunction-Induced Insulin Resistance in Differentiated 3T3-L1 Adipocytes via Inhibition of NF-κB Pathways

1
Department of Bioprocess Engineering, Faculty of Chemical Engineering, University Teknologi Malaysia, Skudai 81310, Malaysia
2
Institute of Bioproduct Development, University Teknologi Malaysia, Skudai 81310, Malaysia
3
Innovation Centre in Agritechnology for Advanced Bioprocessing (ICA), University Teknologi Malaysia, Skudai 81310, Malaysia
4
Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
5
Clinical Investigation Centre, 13th Floor Main Tower, University Malaya Medical Centre, Kuala Lumpur 59100, Malaysia
*
Authors to whom correspondence should be addressed.
Received: 13 September 2014 / Revised: 14 November 2014 / Accepted: 15 November 2014 / Published: 2 December 2014
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

A growing body of evidence suggests that activation of nuclear factor kappa B (NF-κB) signaling pathways is among the inflammatory mechanism involved in the development of insulin resistance and chronic low-grade inflammation in adipose tissues derived from obese animal and human subjects. Nevertheless, little is known about the roles of NF-κB pathways in regulating mitochondrial function of the adipose tissues. In the present study, we sought to investigate the direct effects of celastrol (potent NF-κB inhibitor) upon mitochondrial dysfunction-induced insulin resistance in 3T3-L1 adipocytes. Celastrol ameliorates mitochondrial dysfunction by altering mitochondrial fusion and fission in adipocytes. The levels of oxidative DNA damage, protein carbonylation and lipid peroxidation were down-regulated. Further, the morphology and quantification of intracellular lipid droplets revealed the decrease of intracellular lipid accumulation with reduced lipolysis. Moreover, massive production of the pro-inflammatory mediators tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were markedly depleted. Insulin-stimulated glucose uptake activity was restored with the enhancement of insulin signaling pathways. This study signified that the treatments modulated towards knockdown of NF-κB transcription factor may counteract these metabolic insults exacerbated in our model of synergy between mitochondrial dysfunction and inflammation. These results demonstrate for the first time that NF-κB inhibition modulates mitochondrial dysfunction induced insulin resistance in 3T3-L1 adipocytes. View Full-Text
Keywords: adipocytes; mitochondrial dysfunction; inflammation; oxidative stress; insulin resistance; celastrol; nuclear factor kappa B (NF-κB) adipocytes; mitochondrial dysfunction; inflammation; oxidative stress; insulin resistance; celastrol; nuclear factor kappa B (NF-κB)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Bakar, M.H.A.; Sarmidi, M.R.; Kai, C.K.; Huri, H.Z.; Yaakob, H. Amelioration of Mitochondrial Dysfunction-Induced Insulin Resistance in Differentiated 3T3-L1 Adipocytes via Inhibition of NF-κB Pathways. Int. J. Mol. Sci. 2014, 15, 22227-22257.

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