Faculty Collaboration Database

Mice lacking sialyltransferase ST3Gal-II develop late-onset obesity and insulin resistance. Glycobiology 2017 Jan;27(2):129-139

Date

09/30/2016

Pubmed ID

27683310

Pubmed Central ID

PMC5224593

DOI

10.1093/glycob/cww098

Scopus ID

2-s2.0-85014502638 (requires institutional sign-in at Scopus site)   23 Citations

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.

Author List

Lopez PH, Aja S, Aoki K, Seldin MM, Lei X, Ronnett GV, Wong GW, Schnaar RL

Author

Kazuhiro Aoki PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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