TNF-alpha induces mitochondrial dysfunction in 3T3-L1 adipocytes.
TNF-alpha was the first proinflammatory cytokine identified linking obesity, insulin resistance and chronic inflammation. However, the mechanism of TNF-alpha in the etiology of insulin resistance is still far from clear. Because the mitochondria play an important role in energy metabolism, we investigated whether mitochondrial dysfunction is involved in pathogenesis of TNF-alpha-mediated insulin resistance. First, a fully differentiated insulin-resistant 3T3-L1 adipocyte model was established by incubating with 4 ng/ml TNF-alpha for 4 d, and then the mitochondrial morphology and functions were observed. TNF-alpha treatment induced pronounced morphological changes in the mitochondria, which became smaller and condensed, and some appeared hollow and absent of cristae. Mitochondrial dynamics changes were observed as increased mitofusion protein mfn1 and mitofission protein Drp1 levels compared with controls. No obvious effects on mitochondrial biogenesis were found. PGC-1alpha levels decreased, but no significant changes were found in mtTFA mRNA expression, NRF1mRNA expression and mitochondrial DNA (mtDNA). TNFalpha treatment also led to decreased mitochondrial membrane potential and reduced production of intracellular ATP, as well as accumulation of significant amounts of reactive oxygen species (ROS). Further research is required to determine if mitochondrial dysfunction is involved in the inflammatory mechanism of insulin resistance and may be a potential target for the treatment of insulin resistance.
Chen
Xiao-Hui
XH
Department of Pediatrics, Nanjing Maternal and Child Health Hospital, Nanjing Medical University, Nanjing 210004, China.
Zhao
Ya-Ping
YP
Xue
Mei
M
Ji
Chen-Bo
CB
Gao
Chun-Lin
CL
Zhu
Jin-Gai
JG
Qin
Da-Ni
DN
Kou
Chun-Zhao
CZ
Qin
Xiao-Hong
XH
Tong
Mei-Ling
ML
Guo
Xi-Rong
XR
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D056915:DNA Copy Number Variations / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005947:Glucose / Q000493:pharmacokinetics; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004272:DNA, Mitochondrial; D007328:Insulin; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D005947:Glucose