Mice lacking sialyltransferase ST3Gal-II develop late-onset obesity and insulin resistance.
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.
Department of Pharmacology and Molecular Sciences.
Pablo Hh
PH
Lopez
Center for Metabolic and Obesity Research.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Susan
S
Aja
Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
Kazuhiro
K
Aoki
Center for Metabolic and Obesity Research.|Department of Physiology.
Marcus M
MM
Seldin
Center for Metabolic and Obesity Research.|Department of Physiology.
Xia
X
Lei
Center for Metabolic and Obesity Research.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Physiology.|Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Gabriele V
GV
Ronnett
Center for Metabolic and Obesity Research.|Department of Physiology.
G William
GW
Wong
Department of Pharmacology and Molecular Sciences schnaar@jhu.edu.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ronald L
RL
Schnaar
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005690:Galactose / Q000378:metabolism; D005732:Gangliosides / Q000096:biosynthesis / Q000235:genetics; D005951:Glucose Tolerance Test; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D019158:N-Acetylneuraminic Acid / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D012799:Sialyltransferases / Q000235:genetics*; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
D005732:Gangliosides; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D012799:Sialyltransferases; D019158:N-Acetylneuraminic Acid; D005690:Galactose; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
adipose tissue; ganglioside; hyperglycemia; metabolism; sialic acid
Methods Enzymol. 2006;417:168-85
17132505
J Biol Chem. 2015 Oct 16;290(42):25475-86
26338710
Biochem Biophys Res Commun. 2009 Feb 6;379(2):547-52
19116132
J Biochem. 1984 Mar;95(3):761-70
6725233
Prog Brain Res. 1994;101:XI-XIV
8029441
Hepatology. 2013 Feb;57(2):525-32
22911490
Lipids. 1979 Jan;14(1):52-7
423711
PLoS One. 2015 Jun 23;10(6):e0129645
26102277
OMICS. 2010 Aug;14(4):455-64
20726801
Anal Biochem. 2000 Jul 15;283(1):3-9
10929801
Blood. 2008 Nov 1;112(9):3744-52
18579791
FEBS Lett. 2015 Oct 24;589(21):3221-7
26434718
Nutr Rev. 2007 Jun;65(6 Pt 2):S39-46
17605313
Curr Opin Struct Biol. 2009 Oct;19(5):507-14
19699080
Glycobiology. 2012 Oct;22(10):1289-301
22735313
Glycoconj J. 2014 Dec;31(9):613-22
25351657
Biochim Biophys Acta. 2008 Mar;1780(3):421-33
17991443
J Endocrinol. 2014 Jan 08;220(2):T1-T23
24281010
Chem Phys Lipids. 1976 Sep;17(1):14-21
975445
J Biol Chem. 2002 Feb 1;277(5):3085-92
11707432
Anal Biochem. 1992 May 15;203(1):101-8
1524204
Glycobiology. 2008 Aug;18(8):593-601
18480157
Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13678-83
17699617
Exp Neurol. 2005 Sep;195(1):208-17
15953602
Glycobiology. 2015 Mar;25(3):303-18
25303960
Glycobiology. 2011 Jun;21(6):716-26
21098518
Glycoconj J. 2014 Apr;31(3):193-7
24399479
Glycobiology. 2015 Dec;25(12 ):1323-4
26543186
Cell Signal. 2015 Sep;27(9):1742-50
26022181
Neurochem Res. 2014 Nov;39(11):2262-75
25216715
FASEB J. 2015 Jul;29(7):3040-53
25846372
Methods Enzymol. 1994;230:371-89
7511203
Diabetes. 2007 May;56(5):1210-8
17470562
Handb Exp Pharmacol. 2016;233:51-71
26721672
Methods Enzymol. 1994;230:348-70
8139508
J Mol Biol. 2016 Aug 14;428(16):3325-36
27261254
Blood. 2002 Nov 15;100(10):3618-25
12393657
J Am Soc Mass Spectrom. 2005 Apr;16(4):571-80
15792727
J Biol Chem. 2003 Jul 25;278(30):27896-902
12730204
PLoS One. 2010 Jun 21;5(6):e11239
20574539
Physiol Rev. 2014 Apr;94(2):461-518
24692354
Diabetes. 2007 May;56(5):1341-9
17287460
Methods Enzymol. 2006;417:205-20
17132507
J Biol Chem. 1991 Mar 5;266(7):4531-7
1999434
Future Med Chem. 2015;7(16):2285-99
26511641
Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3445-9
12629211
J Biol Chem. 2002 Mar 29;277(13):11239-46
11782461
PLoS One. 2009;4(3):e4723
19305508
Adv Exp Med Biol. 2010;688:165-84
20919654
J Biol Chem. 2007 Mar 23;282(12):9127-42
17264077