Insulin resistance is a cellular antioxidant defense mechanism.
We know a great deal about the cellular response to starvation via AMPK, but less is known about the reaction to nutrient excess. Insulin resistance may be an appropriate response to nutrient excess, but the cellular sensors that link these parameters remain poorly defined. In the present study we provide evidence that mitochondrial superoxide production is a common feature of many different models of insulin resistance in adipocytes, myotubes, and mice. In particular, insulin resistance was rapidly reversible upon exposure to agents that act as mitochondrial uncouplers, ETC inhibitors, or mitochondrial superoxide dismutase (MnSOD) mimetics. Similar effects were observed with overexpression of mitochondrial MnSOD. Furthermore, acute induction of mitochondrial superoxide production using the complex III antagonist antimycin A caused rapid attenuation of insulin action independently of changes in the canonical PI3K/Akt pathway. These results were validated in vivo in that MnSOD transgenic mice were partially protected against HFD induced insulin resistance and MnSOD+/- mice were glucose intolerant on a standard chow diet. These data place mitochondrial superoxide at the nexus between intracellular metabolism and the control of insulin action potentially defining this as a metabolic sensor of energy excess.
Hoehn
Kyle L
KL
Diabetes and Obesity Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. klh8st@virginia.edu
Salmon
Adam B
AB
Hohnen-Behrens
Cordula
C
Turner
Nigel
N
Hoy
Andrew J
AJ
Maghzal
Ghassan J
GJ
Stocker
Roland
R
Van Remmen
Holly
H
Kraegen
Edward W
EW
Cooney
Greg J
GJ
Richardson
Arlan R
AR
James
David E
DE
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D013481:Superoxides; D000968:Antimycin A; D013482:Superoxide Dismutase