Adipocytes from women with polycystic ovary syndrome demonstrate altered phosphorylation and activity of glycogen synthase kinase 3.
OBJECTIVE
To test the hypothesis that an abnormality in glycogen synthase kinase-3 (GSK3) is a pathogenic factor in polycystic ovary syndrome (PCOS).


METHODS
Prospective experimental study (adipocytes).


METHODS
Tertiary-care academic medical center and teaching hospital.


METHODS
Twenty patients with PCOS and 21 healthy control women.


METHODS
Blood sampling, physical exam, biopsy of SC lower abdominal fat.


METHODS
Glucose transport and protein levels and phosphorylation state of glycogen synthase kinase (GSK)-3alpha and GSK3beta in adipocytes; assessment of GSK3beta activity.


RESULTS
Basal protein levels of glycogen synthase kinase (GSK3alpha and GSK3beta) did not differ between control women and women with PCOS, nor did basal or insulin-stimulated levels of serine phosphorylated GSK3alpha. However, in adipocytes of women with PCOS, insulin stimulation was not associated with increased serine phosphorylation of GSK3beta, in contrast to the case of control women. Tyrosine phosphorylation of GSK3beta also was higher in women with PCOS, compared with in control women. Consistent with the phosphorylation data, GSK3beta activity was elevated in PCOS adipocytes.


CONCLUSIONS
These data suggest that GSK3beta is hyperactivated and resistant to down-regulation by insulin in PCOS. By using physiologic approaches, we demonstrated that abnormal GSK3beta regulation is a potential mechanism for the insulin resistance that is seen in some women with PCOS, which may contribute to their development of the syndrome.
Chang
Wendy
W
Department of Obstetrics and Gynecology, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Goodarzi
Mark O
MO
Williams
Heith
H
Magoffin
Denis A
DA
Pall
Marita
M
Azziz
Ricardo
R
D019325:3-O-Methylglucose / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008875:Middle Aged; D010766:Phosphorylation; D011085:Polycystic Ovary Syndrome / Q000201:enzymology* / Q000503:physiopathology; D011446:Prospective Studies; D055815:Young Adult
D007328:Insulin; D019325:3-O-Methylglucose; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha