Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice - PubMed (original) (raw)

Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice

Kazunari Nohara et al. Am J Physiol Endocrinol Metab. 2013.

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.

Keywords: adiponectin; androgen; insulin resistance; obesity; osteocalcin.

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Figures

Fig. 1.

Neonatal exposure to the androgen testosterone (NT) masculinizes lean tissues and adipose tissues. A: body weight from CF, NTF, and CM mice was determined at the indicated time points (n = 14–28). B: skeletal muscle, heart, and kidney weights were measured at 32 wk (10–23). Body composition was measured by NMR at 20 wk (n = 8). C: 4 fat pad weights [subcutaneous (SC), mesenteric (Mes), perigonadal (PG), and perirenal (PR)] were measured at 8 wk, and visceral fat index was calculated by dividing the total visceral fat pad weight by subcutaneous fat pad weight (n = 6–21). D: 4 fat pad weights were measured at 32 wk; visceral fat index was calculated as described in C (n = 8–23). E and F: lean (E) and fat mass (F) from young control female mice (CF) and mice exposed neonatally to testosterone (NTF) were determined at the indicated time points by quantitative NMR (n = 7–10). Results represent means ± SE. *P < 0.05, **P < 0.01; ***P < 0.001. NTF, CM vs. CF.

Fig. 2.

Adipocyte morphology and function in NTF. A: adipocyte area distribution and average in 32-wk-old PG fat (n = 4). B: lipogenic gene expression was measured in PG fat of 8-wk-old fed mice by quantitative PCR (n = 5–12). C: in vivo lipogenesis was measured by 3H-labeled glucose incorporation into triglyceride in PG fat during euglycemic hyperinsulinemic clamp in 24-wk-old mice (n = 7). D: glucose infusion rate during euglycemic hyperinsulinemic clamp in 24-wk-old mice (n = 6–11). E: serum adiponectin concentrations in 12- to 24-wk-old mice (n = 21–27). Results represent means ± SE. *P < 0.05; **P < 0.01; ***P < 0.001. NTF, CM vs. CF. Srebpf, gene encoding the sterol regulatory element-binding protein-1c; Fasn, gene encoding fatty acid synthase; Acaca, gene encoding acetyl-CoA carboxylase.

Fig. 3.

Osteocalcin (OCN) activity in NTF. Total OCN levels (A), inactive form of osteocalcin GLA13 levels (B), active form of osteocalcin GLU13 levels (C), and ratio of GLU/GLA (n = 11–14; D). Results represent means ± SE. *P < 0.05; **P < 0.01. NTF, CM vs. CF.

Fig. 4.

Developmental gene expression in NTF adipose tissue. A: relative adipocyte cell number was measured in mice from Fig. 3_A_. B_–_D: expression of HoxA5, glypican 4 (Gpc4), and T-box 15 (Tbx15) in SC and PG adipose depots was measured by quantitative PCR at 10 wk of age (n = 5–6). Results represent means ± SE. *P < 0.05. NTF, CM vs. CF.

Fig. 5.

BAT hypofunction in NTF. A: brown adipose tissue (BAT) weights were measured at 9 wk (n = 17–18). B: total NE turnover was measured in BAT at 9 wk (n = 17–18). C: BAT Ucp1 expression in 24-wk-old mice (n = 10–18). D: BAT Ucp1 expression in 20-wk-old mice after 24-h fasting, followed by 6 h of 3 μg/g ip leptin (L) or vehicle (V) treatment (n = 5–6). E and F: daily (E) and mean energy expenditure (F) (heat) was measured at 20 wk by indirect calorimetry (n = 8) and was corrected for body weight (kcal·kg body wt−1·h−1). Results represent means ± SE. *P < 0.05; ***P < 0.001. NTF, CM vs. CF.

Fig. 6.

NTF are predisposed to obesity during androgen excess. SC (A), PG (B), and total fat pad weights (C) were measured in 12-wk-old ovariectomized (OVX) or sham-operated mice treated with testosterone (T) pellets for 8 wk (n = 4–16). D: body fat mass was measured by NMR in 11-wk-old mice (n = 5–16). SC (E), PR (F), Mes (G), PG (H), and total fat pad weight (I) as well as body weight (J) were measured in 10-wk-old mice treated with vehicle or T pellets for 3 wk; n = 8. Results represent means ± SE. *P < 0.05, **P < 0.01, ***P < 0.001 compared with OVX-Sham; #P < 0.05 compared with NTF Sham vs. NTF T; #P < 0.05 and ##P < 0.01 compared with CF (1-way ANOVA).

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Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice - PubMed (original) (raw)