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

Glycobiology. 2017 Jan;27(2):129-139. doi: 10.1093/glycob/cww098. Epub 2016 Sep 28.

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 late-onset 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 insulin-induced 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.

Keywords: adipose tissue; ganglioside; hyperglycemia; metabolism; sialic acid.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Disease Models, Animal
  • Galactose / metabolism
  • Gangliosides / biosynthesis
  • Gangliosides / genetics
  • Glucose Tolerance Test
  • Humans
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance / genetics*
  • Lipid Metabolism / genetics
  • Mice
  • Mice, Knockout
  • N-Acetylneuraminic Acid / genetics
  • N-Acetylneuraminic Acid / metabolism*
  • Obesity / genetics*
  • Obesity / pathology
  • Sialyltransferases / genetics*

Substances

  • Gangliosides
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Sialyltransferases
  • beta-galactoside alpha-2,3-sialyltransferase
  • N-Acetylneuraminic Acid
  • Galactose