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

PABLO HECTOR HORACIO LOPEZ; SUSAN AJA; KAZUKIRO AOKI; MARCUS SELDIN; XIA LEI; GABRIELE RONNET; WILLIAM WONG; RONALD L. SCHNAAR

GLYCOBIOLOGY

OXFORD UNIV PRESS INC

Lugar: Oxford; Año: 2016

0959-6658

Sialyltransferases are a family of 20 gene products in mice and humans that transfer sialic acid from itsactivated 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 3-position of galactose on theGalβ1-3GalNAc 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 insulinresistance. At 3 months of age St3gal2-null mice were the same weight as their wild type counterparts,but by 13 months on standard chow they were visibly obese, 22% heavier and with 37% greaterfat/lean ratio than wild type mice. St3gal2-null mice became hyperglycemic and displayed impairedglucose tolerance by 9 months of age. They had sharply reduced insulin responsiveness despiteequivalent pancreatic islet morphology. Analyses of insulin receptor tyrosine kinase substrate IRS-1and downstream target Akt revealed decreased insulin-induced phosphorylation in adipose tissue butnot liver or skeletal muscle of St3gal2-null mice. Thin-layer chromatography and mass spectrometryrevealed altered ganglioside profiles in the adipose tissue of St3gal2-null mice compared to wild typelittermates. Metabolically, St3gal2-null mice display a reduced respiratory exchange ratio compared towild type mice, indicating a preference for lipid oxidation as an energy source. Despite their alteredmetabolism, St3gal2-null mice were hyperactive. We conclude that altered ganglioside expression inadipose tissue results in diminished insulin receptor sensitivity and late onset obesity.