Syntaxin 4 heterozygous knockout mice develop muscle insulin resistance
Chunmei Yang, … , Gerald I. Shulman, Jeffrey E. Pessin
Chunmei Yang, … , Gerald I. Shulman, Jeffrey E. Pessin
Published May 15, 2001
Citation Information: J Clin Invest. 2001;107(10):1311-1318. https://doi.org/10.1172/JCI12274.
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Article

Syntaxin 4 heterozygous knockout mice develop muscle insulin resistance

Abstract

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.

Authors

Chunmei Yang, Kenneth J. Coker, Jason K. Kim, Silvia Mora, Debbie C. Thurmond, Ann C. Davis, Baoli Yang, Roger A. Williamson, Gerald I. Shulman, Jeffrey E. Pessin

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Generation of heterozygous syntaxin 4–knockout mouse by homologous recom...
Generation of heterozygous syntaxin 4–knockout mouse by homologous recombination in ES cells. (a) Schematic representation of the syntaxin 4 genomic structure: Exons 1–11 are represented by the numbered, filled boxes. The relative position of the diagnostic probe is also indicated as are the translational start and stop sites at exons 1 and 10, respectively. (b) Schematic representation of the syntaxin 4 targeting vector. The 2.8-kb SpeI-NheI fragment (5′-homology) and the 3.0-kb HindIII-HindIII fragment (3′-homology) that allowed homologous recombination with the genomic locus are indicated as is the neoR gene, which replaced exons 1–5. The thymidine kinase gene is labeled HSVtk. (c) Schematic representation of the targeted syntaxin 4 allele. (d) Southern blot analysis of ES and mouse liver DNA digested with EcoRI (RI) and probed with the diagnostic D/H probe indicated. The wild-type allele generates a 9.5-kb EcoRI fragment, whereas the targeted allele produces a 14-kb EcoRI fragment. (e) Homozygotic disruption of the syntaxin 4 gene causes embryonic lethality. The total number of heterozygotic crosses (186 births) resulting in the three genotypes are indicated.