title: Amelioration of mitochondrial dysfunction-induced insulin resistance in differentiated 3T3-L1 adipocytes via inhibition of NF-κB pathways.
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.
authors.affiliation: Department of Bioprocess Engineering, Faculty of Chemical Engineering, University Teknologi Malaysia, Skudai 81310, Malaysia. mhafizi55@live.utm.my.
authors.forename: Mohamad Hafizi Abu
authors.initials: MH
authors.lastname: Bakar
authors.affiliation: Institute of Bioproduct Development, University Teknologi Malaysia, Skudai 81310, Malaysia. mroji@ibd.utm.my.
authors.forename: Mohamad Roji
authors.initials: MR
authors.lastname: Sarmidi
authors.affiliation: Department of Bioprocess Engineering, Faculty of Chemical Engineering, University Teknologi Malaysia, Skudai 81310, Malaysia. harisun@ibd.utm.my.
authors.forename: Cheng Kian
authors.initials: CK
authors.lastname: Kai
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia. hasnizazh@ummc.edu.my.
authors.forename: Hasniza Zaman
authors.initials: HZ
authors.lastname: Huri
authors.affiliation: Innovation Centre in Agritechnology for Advanced Bioprocessing (ICA), University Teknologi Malaysia, Skudai 81310, Malaysia. harisun@ibd.utm.my.
authors.forename: Harisun
authors.initials: H
authors.lastname: Yaakob
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D053583:Interleukin-1beta / Q000096:biosynthesis; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D009840:Oligomycins / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D053978:Pentacyclic Triterpenes; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; D053583:Interleukin-1beta; D016328:NF-kappa B; D009840:Oligomycins; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D005947:Glucose; C050414:celastrol