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

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

Author information

1
Department of Pharmacology and Molecular Sciences.
2
Center for Metabolic and Obesity Research.
3
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4
Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
5
Department of Physiology.
6
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
7
Department of Pharmacology and Molecular Sciences schnaar@jhu.edu.

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

PMID:
27683310
PMCID:
PMC5224593
DOI:
10.1093/glycob/cww098
[Indexed for MEDLINE]
Free PMC Article

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