Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance.
Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and is strongly associated with obesity. Increased concentrations of intracellular fatty acid metabolites have been postulated to interfere with insulin signaling by activation of a serine kinase cascade involving PKCtheta in skeletal muscle. Uncoupling protein 3 (UCP3) has been postulated to dissipate the mitochondrial proton gradient and cause metabolic inefficiency. We therefore hypothesized that overexpression of UCP3 in skeletal muscle might protect against fat-induced insulin resistance in muscle by conversion of intramyocellular fat into thermal energy. Wild-type mice fed a high-fat diet were markedly insulin resistant, a result of defects in insulin-stimulated glucose uptake in skeletal muscle and hepatic insulin resistance. Insulin resistance in these tissues was associated with reduced insulin-stimulated insulin receptor substrate 1- (IRS-1-) and IRS-2-associated PI3K activity in muscle and liver, respectively. In contrast, UCP3-overexpressing mice were completely protected against fat-induced defects in insulin signaling and action in these tissues. Furthermore, these changes were associated with a lower membrane-to-cytosolic ratio of diacylglycerol and reduced PKCtheta activity in whole-body fat-matched UCP3 transgenic mice. These results suggest that increasing mitochondrial uncoupling in skeletal muscle may be an excellent therapeutic target for type 2 diabetes mellitus.
Choi
Cheol Soo
CS
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06536-9812, USA.
Fillmore
Jonathan J
JJ
Kim
Jason K
JK
Liu
Zhen-Xiang
ZX
Kim
Sheene
S
Collier
Emily F
EF
Kulkarni
Ameya
A
Distefano
Alberto
A
Hwang
Yu-Jin
YJ
Kahn
Mario
M
Chen
Yan
Y
Yu
Chunli
C
Moore
Irene K
IK
Reznick
Richard M
RM
Higashimori
Takamasa
T
Shulman
Gerald I
GI
D055372:AMP-Activated Protein Kinases; D000375:Aging / Q000502:physiology; D000818:Animals; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006728:Hormones / Q000097:blood; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000071247:Uncoupling Protein 3; D015430:Weight Gain
D006728:Hormones; D007328:Insulin; D007473:Ion Channels; D007527:Isoenzymes; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; C000604392:UCP3 protein, human; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; C494922:Akt2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D055372:AMP-Activated Protein Kinases