Enhanced insulin sensitivity in mice lacking ganglioside GM3.
Gangliosides are sialic acid-containing glycosphingolipids that are present on all mammalian plasma membranes where they participate in recognition and signaling activities. We have established mutant mice that lack GM3 synthase (CMP-NeuAc:lactosylceramide alpha2,3-sialyltransferase; EC 2.4.99.-). These mutant mice were unable to synthesize GM3 ganglioside, a simple and widely distributed glycosphingolipid. The mutant mice were viable and appeared without major abnormalities but showed a heightened sensitivity to insulin. A basis for the increased insulin sensitivity in the mutant mice was found to be enhanced insulin receptor phosphorylation in skeletal muscle. Importantly, the mutant mice were protected from high-fat diet-induced insulin resistance. Our results show that GM3 ganglioside is a negative regulator of insulin signaling, making it a potential therapeutic target in type 2 diabetes.
Yamashita
Tadashi
T
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, 10 Center Drive, Bethesda, MD 20892, USA.
Hashiramoto
Akira
A
Haluzik
Martin
M
Mizukami
Hiroki
H
Beck
Shoshannah
S
Norton
Aaron
A
Kono
Mari
M
Tsuji
Shuichi
S
Daniotti
Jose Luis
JL
Werth
Norbert
N
Sandhoff
Roger
R
Sandhoff
Konrad
K
Proia
Richard L
RL
D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D005679:G(M3) Ganglioside / Q000172:deficiency*; D018390:Gene Targeting; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D012799:Sialyltransferases / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction
D004041:Dietary Fats; D005679:G(M3) Ganglioside; D012799:Sialyltransferases; C021343:haematoside synthetase; D011972:Receptor, Insulin