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.

Mitochondrial Lon protease - depleted HeLa cells exhibit proteome modifications related to protein quality control, stress response and energy metabolism

“…In contrast, treatments with 2-DG and oligomycin, that are inhibiting glycolysis or mitochondrial respiration respectively, did not result in increased protein oxidation either in control or in Londepleted cells. Similar observations or, on the contrary, increased oxidative stress have already been noted with both reagents [24], [25], [26], [27], [28], [29]. Concerning the 3% oxygen and the hypoxia-mimetic DFO treatments, Lon knockdown is associated with no significant change in protein carbonylation in the first case and with more carbonylated proteins in the second case.…”

Reduced expression of Twist 1 is protective against insulin resistance of adipocytes and involves mitochondrial dysfunction

“…In adipocytes, mitochondrial dysfunction sometimes induces IR. The application of Celastrol, potent NF-κB inhibitor, was reported to modulate mitochondrial dysfunction-induced IR in 3T3-L1 adipocytes 38 . Mitochondrial dysfunction was also believed to constitute a mechanistic link between various genes, such as Nat1, and IR 39 .…”

Sesamol ameliorates diet‐induced obesity in C57BL/6J mice and suppresses adipogenesis in 3T3‐L1 cells via regulating mitochondria‐lipid metabolism

“…3T3‐L1 preadipocytes were provided by Kunming Institute of Zoology, Chinese Academy of Sciences (Kunming, China) and cultured in DMEM (Gibco Co., USA) supplemented with 10% bovine calf serum, 100 IU/mL penicillin, and 100 μg/mL streptomycin at 37°C in a humidified atmosphere with 5% CO 2 . The protocol was modified from previous research . Briefly, the cells were incubated for 48 h before undergoing full differentiation.…”