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

• Autores: Lopez, Pablo; Aja, Susan; Aoki, Kazuhiro; Seldin, Marcus M.; Lei, Xia; Ronnett, Gabriele V; Wong, G. William; Schnaar, Ronald L.
• Año de publicación: 2017
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: ADIPOSE TISSUE; GANGLIOSIDE; HYPERGLYCEMIA; METABOLISM; SIALIC ACID
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Lopez, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Johns Hopkins University School of Medicine; Estados Unidos
Fil: Aja, Susan. Johns Hopkins University School of Medicine; Estados Unidos
Fil: Aoki, Kazuhiro. University of Georgia; Grecia
Fil: Seldin, Marcus M.. Johns Hopkins University School of Medicine; Estados Unidos
Fil: Lei, Xia. Johns Hopkins University School of Medicine; Estados Unidos
Fil: Ronnett, Gabriele V. Johns Hopkins University School of Medicine; Estados Unidos
Fil: Wong, G. William. Johns Hopkins University School of Medicine; Estados Unidos
Fil: Schnaar, Ronald L.. Johns Hopkins University School of Medicine; Estados Unidos