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.
Highlights
In recent years, the roles of mitochondrial dysfunction-induced inflammation towards progression of insulin resistance, the forerunner of type 2 diabetes mellitus, have acquired important new dimensions [1,2,3,4].a number of studies have discovered that the impairments of mitochondrial functions in skeletal muscles, liver and adipose tissues of both human and animal disease subjects are etiologically associated with low-grade chronic inflammation [5,6]
We used differentiated 3T3-L1 adipocytes as an in vitro cellular model to study the ameliorative properties of celastrol on mitochondrial dysfunction induced by mitochondrial inhibitor oligomycin that can lead to insulin resistance
The cell viability of 3T3-L1 adipocytes incubated with celastrol discovered that the significant decline of cell viability was exhibited at the concentration of 10, 20 and 30 μM by 37%, 48% and 56%, respectively
Summary
The roles of mitochondrial dysfunction-induced inflammation towards progression of insulin resistance, the forerunner of type 2 diabetes mellitus, have acquired important new dimensions [1,2,3,4]. A number of studies have discovered that the impairments of mitochondrial functions in skeletal muscles, liver and adipose tissues of both human and animal disease subjects are etiologically associated with low-grade chronic inflammation [5,6]. In light of data indicating a pathophysiologic role of mitochondrial dysfunction in the occurrence of inflammation and insulin resistance, it is intriguing to hypothesize that the metabolic adaptations observed in these target tissues may affect the whole body metabolism. It is becoming clear that the derangements of cellular inflammatory mediators are inextricably linked to the development of oxidative stress and reduced mitochondrial functions in insulin resistance state. Adipose tissues are the group of heterogeneous mix of adipocytes, which constitute a wide range of fat tissues, immune cells, stroma-vascular cells, such as fibroblast, endothelial cells and pericytes [8]
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