Syntaxin 4 heterozygous knockout mice develop muscle insulin resistance.
To investigate the physiological function of syntaxin 4 in the regulation of GLUT4 vesicle trafficking, we used homologous recombination to generate syntaxin 4-knockout mice. Homozygotic disruption of the syntaxin 4 gene results in early embryonic lethality, whereas heterozygous knockout mice, Syn4(+/-), had normal viability with no significant impairment in growth, development, or reproduction. However, the Syn4(+/-) mice manifested impaired glucose tolerance with a 50% reduction in whole-body glucose uptake. This defect was attributed to a 50% reduction in skeletal muscle glucose transport determined by 2-deoxyglucose uptake during hyperinsulinemic-euglycemic clamp procedures. In parallel, insulin-stimulated GLUT4 translocation in skeletal muscle was also significantly reduced in these mice. In contrast, Syn4(+/-) mice displayed normal insulin-stimulated glucose uptake and metabolism in adipose tissue and liver. Together, these data demonstrate that syntaxin 4 plays a critical physiological role in insulin-stimulated glucose uptake in skeletal muscle. Furthermore, reduction in syntaxin 4 protein levels in this tissue can account for the impairment in whole-body insulin-stimulated glucose metabolism in this animal model.
Yang
C
C
Department of Physiology and Biophysics, The University of Iowa, Iowa City, Iowa 52242, USA.
Coker
K J
KJ
Kim
J K
JK
Mora
S
S
Thurmond
D C
DC
Davis
A C
AC
Yang
B
B
Williamson
R A
RA
Shulman
G I
GI
Pessin
J E
JE
D017667:Adipocytes / Q000502:physiology; D002001:Adipose Tissue, Brown; D000818:Animals; D001692:Biological Transport; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis; D006579:Heterozygote; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000502:physiology*; D050765:Qa-SNARE Proteins
D051275:Glucose Transporter Type 4; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D050765:Qa-SNARE Proteins; C495693:Slc2a4 protein, mouse; D006003:Glycogen; D005947:Glucose