Mice lacking sialyltransferase ST3Gal-II develop late-onset obesity and insulin resistance

Pablo H.H. Lopez, Susan Aja, Kazuhiro Aoki, Marcus M. Seldin, Xia Lei, Gabriele V Ronnett, G. William Wong, Ronald L. Schnaar

Research output: Contribution to journalArticlepeer-review

Abstract

Sialyltransferases are a family of 20 gene products in mice and humans that transfer sialic acid from its activated precursor, CMP-sialic acid, to the terminus of glycoprotein and glycolipid acceptors. ST3Gal-II (coded by the St3gal2 gene) transfers sialic acid preferentially to the three positions of galactose on the Galβ1-3GalNAc terminus of gangliosides GM1 and GD1b to synthesize GD1a and GT1b, respectively. Mice with a targeted disruption of St3gal2 unexpectedly displayed lateonset obesity and insulin resistance. At 3 months of age, St3gal2-null mice were the same weight as their wild type (WT) counterparts, but by 13 months on standard chow they were visibly obese, 22% heavier and with 37% greater fat/lean ratio than WT mice. St3gal2-null mice became hyperglycemic and displayed impaired glucose tolerance by 9 months of age. They had sharply reduced insulin responsiveness despite equivalent pancreatic islet morphology. Analyses of insulin receptor (IR) tyrosine kinase substrate IRS-1 and downstream target Akt revealed decreased insulininduced phosphorylation in adipose tissue but not liver or skeletal muscle of St3gal2-null mice. Thin-layer chromatography and mass spectrometry revealed altered ganglioside profiles in the adipose tissue of St3gal2-null mice compared to WT littermates. Metabolically, St3gal2-null mice display a reduced respiratory exchange ratio compared to WT mice, indicating a preference for lipid oxidation as an energy source. Despite their altered metabolism, St3gal2-null mice were hyperactive. We conclude that altered ganglioside expression in adipose tissue results in diminished IR sensitivity and late-onset obesity.

Original languageEnglish (US)
Pages (from-to)129-139
Number of pages11
JournalGlycobiology
Volume27
Issue number1
DOIs
StatePublished - 2017

Keywords

  • Adipose tissue
  • Ganglioside
  • Hyperglycemia
  • Metabolism
  • Sialic acid

ASJC Scopus subject areas

  • Biochemistry

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