Prenatal androgen exposure programs metabolic dysfunction in female mice.
Polycystic ovary syndrome (PCOS) is a common fertility disorder with metabolic sequelae. Our laboratory previously characterized reproductive phenotypes in a prenatally androgenized (PNA) mouse model for PCOS. PNA mice exhibited elevated testosterone and LH levels, irregular estrous cycles, and neuroendocrine abnormalities suggesting increased central drive to the reproductive system. In this study, we examined metabolic characteristics of female PNA mice. PNA mice exhibited increased fasting glucose and impaired glucose tolerance (IGT) that were independent of age and were not associated with changes in body composition or peripheral insulin sensitivity. IGT was associated with defects in pancreatic islet function leading to an impaired response to high glucose, consistent with impaired insulin secretion. Exposure of isolated pancreatic islets to androgen in vitro demonstrated an impaired response to glucose stimulation similar to that in PNA mice, suggesting androgens may have activational in addition to organizational effects on pancreatic islet function. PNA mice also exhibited increased size of visceral adipocytes, suggesting androgen-programed differences in adipocyte differentiation and/or function. These studies demonstrate that in addition to causing reproductive axis abnormalities, in utero androgen exposure can induce long-term metabolic alterations in female mice.
Roland
Alison V
AV
Departments of Medicine Cell Biology, University of Virginia, PO Box 800578, Charlottesville, Virginia 22908, USA.
Nunemaker
Craig S
CS
Keller
Susanna R
SR
Moenter
Suzanne M
SM
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000375:Aging; D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology*; D005260:Female; D018149:Glucose Intolerance / Q000139:chemically induced; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D011085:Polycystic Ovary Syndrome / Q000139:chemically induced*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*
D000728:Androgens; D007328:Insulin; D013196:Dihydrotestosterone; D002118:Calcium