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: Mohamad Hafizi Abu Bakar, Mohamad Roji Sarmidi, Cheng Kian Kai, Hasniza Zaman Huri, Harisun Yaakob
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 15 Issue 12 Pg. 22227-57 (Dec 02 2014) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 25474091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glucose Transporter Type 1
• Glucose Transporter Type 4
• Insulin
• Interleukin-1beta
• NF-kappa B
• Oligomycins
• Pentacyclic Triterpenes
• Triterpenes
• Tumor Necrosis Factor-alpha
• Glucose
• celastrol

Topics

• 3T3-L1 Cells
• Adipocytes (cytology, drug effects, metabolism)
• Animals
• Cell Differentiation (drug effects)
• Cell Survival (drug effects)
• Electron Transport (drug effects)
• Glucose (metabolism)
• Glucose Transporter Type 1 (metabolism)
• Glucose Transporter Type 4 (metabolism)
• Humans
• Insulin (pharmacology)
• Insulin Resistance
• Interleukin-1beta (biosynthesis)
• Intracellular Space (drug effects, metabolism)
• Lipolysis (drug effects)
• Mice
• Mitochondria (drug effects, metabolism, pathology)
• NF-kappa B (metabolism)
• Oligomycins (chemistry, pharmacology)
• Oxidative Stress (drug effects)
• Pentacyclic Triterpenes
• Signal Transduction (drug effects)
• Triterpenes (chemistry, pharmacology)
• Tumor Necrosis Factor-alpha (biosynthesis)