title: Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice.
abstract: Among women, the polycystic ovarian syndrome (PCOS) is considered a form of metabolic syndrome with reproductive abnormalities. Women with PCOS show increased sympathetic tone, visceral adiposity with enlarged adipocytes, hypoadiponectinemia, insulin resistance, glucose intolerance, increased inactive osteocalcin, and hypertension. Excess fetal exposure to androgens has been hypothesized to play a role in the pathogenesis of PCOS. Previously, we showed that neonatal exposure to the androgen testosterone (NT) programs leptin resistance in adult female mice. Here, we studied the impact of NT on lean and adipose tissues, sympathetic tone in cardiometabolic tissues, and the development of metabolic dysfunction in mice. Neonatally androgenized adult female mice (NTF) displayed masculinization of lean tissues with increased cardiac and skeletal muscle as well as kidney masses. NTF mice showed increased and dysfunctional white adipose tissue with increased sympathetic tone in both visceral and subcutaneous fat as well as increased number of enlarged and insulin-resistant adipocytes that displayed altered expression of developmental genes and hypoadiponectinemia. NTF exhibited dysfunctional brown adipose tissue with increased mass and decreased energy expenditure. They also displayed decreased undercarboxylated and active osteocalcin and were predisposed to obesity during chronic androgen excess. NTF showed increased renal sympathetic tone associated with increased blood pressure, and they developed glucose intolerance and insulin resistance. Thus, developmental exposure to testosterone in female mice programs features of cardiometabolic dysfunction, as can be observed in women with PCOS, including increased sympathetic tone, visceral adiposity, insulin resistance, prediabetes, and hypertension.
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine, and.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Nohara
authors.forename: Rizwana S
authors.initials: RS
authors.lastname: Waraich
authors.forename: Suhuan
authors.initials: S
authors.lastname: Liu
authors.forename: Mathieu
authors.initials: M
authors.lastname: Ferron
authors.forename: Aurélie
authors.initials: A
authors.lastname: Waget
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Meyers
authors.forename: Gérard
authors.initials: G
authors.lastname: Karsenty
authors.forename: Rémy
authors.initials: R
authors.lastname: Burcelin
authors.forename: Franck
authors.initials: F
authors.lastname: Mauvais-Jarvis
mesh_terms: D002001:Adipose Tissue, Brown / Q000254:growth & development / Q000378:metabolism; D052436:Adipose Tissue, White / Q000254:growth & development / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006977:Hypertension, Renal / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D050152:Intra-Abdominal Fat / Q000378:metabolism; D024821:Metabolic Syndrome / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011085:Polycystic Ovary Syndrome / Q000378:metabolism*; D011236:Prediabetic State / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000254:growth & development / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000728:Androgens; D013739:Testosterone
keywords: adiponectin; androgen; insulin resistance; obesity; osteocalcin