PMID- 22742515
OWN - NLM
STAT- MEDLINE
DCOM- 20130426
LR  - 20211021
IS  - 1573-4935 (Electronic)
IS  - 0144-8463 (Print)
IS  - 0144-8463 (Linking)
VI  - 32
IP  - 5
DP  - 2012 Oct
TI  - Mitochondrial dysfunction in insulin resistance: differential contributions of 
      chronic insulin and saturated fatty acid exposure in muscle cells.
PG  - 465-78
LID - 10.1042/BSR20120034 [doi]
AB  - Mitochondrial dysfunction has been associated with insulin resistance, obesity 
      and diabetes. Hyperinsulinaemia and hyperlipidaemia are hallmarks of the 
      insulin-resistant state. We sought to determine the contributions of high insulin 
      and saturated fatty acid exposure to mitochondrial function and biogenesis in 
      cultured myocytes. Differentiated C2C12 myotubes were left untreated or exposed 
      to chronic high insulin or high palmitate. Mitochondrial function was determined 
      assessing: oxygen consumption, mitochondrial membrane potential, ATP content and 
      ROS (reactive oxygen species) production. We also determined the expression of 
      several mitochondrial genes. Chronic insulin treatment of myotubes caused insulin 
      resistance with reduced PI3K (phosphoinositide 3-kinase) and ERK 
      (extracellular-signal-regulated kinase) signalling. Insulin treatment increased 
      oxygen consumption but reduced mitochondrial membrane potential and ROS 
      production. ATP cellular levels were maintained through an increased glycolytic 
      rate. The expression of mitochondrial OXPHOS (oxidative phosphorylation) subunits 
      or Mfn-2 (mitofusin 2) were not significantly altered in comparison with 
      untreated cells, whereas expression of PGC-1alpha (peroxisome-proliferator-activated 
      receptor gamma co-activator-1alpha) and UCPs (uncoupling proteins) were reduced. In 
      contrast, saturated fatty acid exposure caused insulin resistance, reducing PI3K 
      (phosphoinositide 3-kinase) and ERK (extracellular-signal-regulated kinase) 
      activation while increasing activation of stress kinases JNK (c-Jun N-terminal 
      kinase) and p38. Fatty acids reduced oxygen consumption and mitochondrial 
      membrane potential while up-regulating the expression of mitochondrial ETC 
      (electron chain complex) protein subunits and UCP proteins. Mfn-2 expression was 
      not modified by palmitate. Palmitate-treated cells also showed a reduced 
      glycolytic rate. Taken together, our findings indicate that chronic insulin and 
      fatty acid-induced insulin resistance differentially affect mitochondrial 
      function. In both conditions, cells were able to maintain ATP levels despite the 
      loss of membrane potential; however, different protein expression suggests 
      different adaptation mechanisms.
FAU - Yang, Chenjing
AU  - Yang C
AD  - Department of Cellular and Molecular Physiology, Institute of Translational 
      Medicine, University of Liverpool, Liverpool, U.K.
FAU - Aye, Cho Cho
AU  - Aye CC
FAU - Li, Xiaoxin
AU  - Li X
FAU - Diaz Ramos, Angels
AU  - Diaz Ramos A
FAU - Zorzano, Antonio
AU  - Zorzano A
FAU - Mora, Silvia
AU  - Mora S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biosci Rep
JT  - Bioscience reports
JID - 8102797
RN  - 0 (Fatty Acids)
RN  - 0 (Insulin)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Uncoupling Agents)
RN  - 2V16EO95H1 (Palmitic Acid)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - EC 3.6.1.- (Mfn2 protein, mouse)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - Fatty Acids/*pharmacology
MH  - GTP Phosphohydrolases/genetics/metabolism
MH  - Gene Expression Regulation
MH  - Insulin/*pharmacology
MH  - Insulin Resistance/*physiology
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mice
MH  - Mitochondria/drug effects/genetics/*metabolism
MH  - Mitochondrial Proteins/genetics/metabolism
MH  - Muscle Fibers, Skeletal/cytology/drug effects
MH  - Muscle, Skeletal/*drug effects/*metabolism
MH  - Palmitic Acid/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Signal Transduction
MH  - Uncoupling Agents/pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC3475448
EDAT- 2012/06/30 06:00
MHDA- 2013/04/27 06:00
PMCR- 2012/08/08
CRDT- 2012/06/30 06:00
PHST- 2012/06/30 06:00 [entrez]
PHST- 2012/06/30 06:00 [pubmed]
PHST- 2013/04/27 06:00 [medline]
PHST- 2012/08/08 00:00 [pmc-release]
AID - BSR20120034 [pii]
AID - 10.1042/BSR20120034 [doi]
PST - ppublish
SO  - Biosci Rep. 2012 Oct;32(5):465-78. doi: 10.1042/BSR20120034.