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.

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

“…25 , 26 Excess prenatal androgens (PNA) during this period induce a hypertensive phenotype in adulthood that is characterized by impaired blood flow in the vascular endothelium 12 , increased blood volume 27 , and increased blood pressure in adult females and males. 28 , 29 However, the mechanism by which androgens induce this hypertension is not clear. Interestingly, studies of microbial transplantation have demonstrated that the microbiome affects blood pressure.…”

Developmental androgenization programs metabolic dysfunction in adult mice

“…When these mice matured, we compared female mice exposed to neonatal testosterone (NTF) with control females (CF), control males (CM), and male mice exposed to neonatal testosterone (NTM). [6][7][8] Importantly, littermate males and females were androgenized at the same time, thereby facilitating comparison of their phenotypes in adulthood.…”

“…7 showed increased and dysfunctional white adipose tissue with an increased number of enlarged and insulin resistant adipocytes as well as hypoadiponectinemia. They also displayed bone dysfunction with decreased undercarboxylated and active osteocalcin.…”

“…However, classical genetic markers of adipose differentiation (CEBPs and PPARγ) were not increased. 7 Like muscle and bone, adipose tissue is mesodermal in origin. 9 In mice, adipose tissue development occurs during the first two weeks of neonatal life.…”

“…7 It is still unknown, however, whether the origin of this increased fat sympathetic tone is central or peripheral. Indeed, in mice, activation of central sympathetic efferent to adipose tissue is known to reduce cell numbers and decrease both lipogenesis and fat mass.…”