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In an Ovine Model of Polycystic Ovary Syndrome (PCOS) Prenatal Androgens Suppress Female Fetal Renal Gluconeogenesis.

Connolly F, Rae MT, Späth K, Boswell L, McNeilly AS, Duncan WC - PLoS ONE (2015)

Bottom Line: PEPCK and G6PC were localised to fetal hepatocytes but maternal androgens had no effect on female or male fetuses.The tissue specific effects may be related to the increased expression of ESR1 (P<0.01) and AR (P<0.05) in the kidney when compared to the fetal liver.These data further highlight the fetal and sexual dimorphic effects of maternal androgenisation, an antecedent to adult disease and the plasticity of fetal development.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Reproductive Health, the University of Edinburgh, Edinburgh, United Kingdom.

ABSTRACT
Increased maternal androgen exposure during pregnancy programmes a polycystic ovary syndrome (PCOS)-like condition, with metabolic dysfunction, in adult female offspring. Other in utero exposures associated with the development of insulin resistance, such as intrauterine growth restriction and exposure to prenatal glucocorticoids, are associated with altered fetal gluconeogenesis. We therefore aimed to assess the effect of maternal androgenisation on the expression of PEPCK and G6PC in the ovine fetus. Pregnant Scottish Greyface sheep were treated with twice weekly testosterone propionate (TP; 100mg) or vehicle control from day 62 to day 102 of gestation. At day 90 and day 112 fetal plasma and liver and kidney tissue was collected for analysis. PEPCK and G6PC expression were analysed by quantitative RT-PCR, immunohistochemistry and western blotting. PEPCK and G6PC were localised to fetal hepatocytes but maternal androgens had no effect on female or male fetuses. PEPCK and G6PC were also localised to the renal tubules and renal PEPCK (P<0.01) and G6PC (P = 0.057) were lower in females after prenatal androgenisation with no change in male fetuses. These tissue and sex specific observations could not be explained by alterations in fetal insulin or cortisol. The sexual dimorphism may be related to the increase in circulating estrogen (P<0.01) and testosterone (P<0.001) in females but not males. The tissue specific effects may be related to the increased expression of ESR1 (P<0.01) and AR (P<0.05) in the kidney when compared to the fetal liver. After discontinuation of maternal androgenisation female fetal kidney PEPCK expression normalised. These data further highlight the fetal and sexual dimorphic effects of maternal androgenisation, an antecedent to adult disease and the plasticity of fetal development.

No MeSH data available.


Related in: MedlinePlus

Role of insulin and glucagon.Serum insulin levels, measured by ELISA, in d90 female controls (Cont) and prenatally androgenised (TP) females (white) and males (black bars) (A). Modulators of insulin action; IR (B), IRS1 (C), and IGF1 (D) and measurement of glucagon signalling pathway ADCY5 (E) and ADCY6 (F) in the kidney (light bars) and liver (dark bars) quantified by qRT-PCR analysis, in d90 control (Cont) and TP exposed females. Values represent mean ±S.E.M.*P<0.05, ** P<0.01, *** P<0.001.
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pone.0132113.g003: Role of insulin and glucagon.Serum insulin levels, measured by ELISA, in d90 female controls (Cont) and prenatally androgenised (TP) females (white) and males (black bars) (A). Modulators of insulin action; IR (B), IRS1 (C), and IGF1 (D) and measurement of glucagon signalling pathway ADCY5 (E) and ADCY6 (F) in the kidney (light bars) and liver (dark bars) quantified by qRT-PCR analysis, in d90 control (Cont) and TP exposed females. Values represent mean ±S.E.M.*P<0.05, ** P<0.01, *** P<0.001.

Mentions: As insulin is a negative regulator of gluconeogenesis, fetal insulin concentrations were measured. In female fetuses circulating insulin was decreased by prenatal androgenisation while there were no differences in male fetuses (Fig 3A). Insulin could explain sexually dimorphic changes but a reduction in insulin would not be expected to drive a lower PEPCK expression. In females there was no change in IR (Fig 3B) expression but an increase in IRS1 expression (P<0.01; Fig 3C) in the kidney. In the female liver the same increase in IRS1 (P<0.05; Fig 3C) and lack of alteration of IR (Fig 3B) was also noted. There was no effect of IGF1 expression, which was higher in the fetal liver than the kidney (Fig 3D). Glucagon works to increase PEPCK activity and ADCY5 and ADCY6 are downstream targets of the glucagon pathway. Prenatal androgenisation did not alter renal or hepatic expression of ADCY5, nor was there a tissue specific altered pattern of expression (Fig 3E). Although ADCY6 had higher levels of expression in the fetal kidney than liver (P<0.001) its expression was not altered in response to prenatal androgen treatment (Fig 3F). Overall these results are not consistent with insulin or glucagon having a key role in the sex and tissue specific regulation of gluconeogenesis seen in prenatal androgenisation.


In an Ovine Model of Polycystic Ovary Syndrome (PCOS) Prenatal Androgens Suppress Female Fetal Renal Gluconeogenesis.

Connolly F, Rae MT, Späth K, Boswell L, McNeilly AS, Duncan WC - PLoS ONE (2015)

Role of insulin and glucagon.Serum insulin levels, measured by ELISA, in d90 female controls (Cont) and prenatally androgenised (TP) females (white) and males (black bars) (A). Modulators of insulin action; IR (B), IRS1 (C), and IGF1 (D) and measurement of glucagon signalling pathway ADCY5 (E) and ADCY6 (F) in the kidney (light bars) and liver (dark bars) quantified by qRT-PCR analysis, in d90 control (Cont) and TP exposed females. Values represent mean ±S.E.M.*P<0.05, ** P<0.01, *** P<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492923&req=5

pone.0132113.g003: Role of insulin and glucagon.Serum insulin levels, measured by ELISA, in d90 female controls (Cont) and prenatally androgenised (TP) females (white) and males (black bars) (A). Modulators of insulin action; IR (B), IRS1 (C), and IGF1 (D) and measurement of glucagon signalling pathway ADCY5 (E) and ADCY6 (F) in the kidney (light bars) and liver (dark bars) quantified by qRT-PCR analysis, in d90 control (Cont) and TP exposed females. Values represent mean ±S.E.M.*P<0.05, ** P<0.01, *** P<0.001.
Mentions: As insulin is a negative regulator of gluconeogenesis, fetal insulin concentrations were measured. In female fetuses circulating insulin was decreased by prenatal androgenisation while there were no differences in male fetuses (Fig 3A). Insulin could explain sexually dimorphic changes but a reduction in insulin would not be expected to drive a lower PEPCK expression. In females there was no change in IR (Fig 3B) expression but an increase in IRS1 expression (P<0.01; Fig 3C) in the kidney. In the female liver the same increase in IRS1 (P<0.05; Fig 3C) and lack of alteration of IR (Fig 3B) was also noted. There was no effect of IGF1 expression, which was higher in the fetal liver than the kidney (Fig 3D). Glucagon works to increase PEPCK activity and ADCY5 and ADCY6 are downstream targets of the glucagon pathway. Prenatal androgenisation did not alter renal or hepatic expression of ADCY5, nor was there a tissue specific altered pattern of expression (Fig 3E). Although ADCY6 had higher levels of expression in the fetal kidney than liver (P<0.001) its expression was not altered in response to prenatal androgen treatment (Fig 3F). Overall these results are not consistent with insulin or glucagon having a key role in the sex and tissue specific regulation of gluconeogenesis seen in prenatal androgenisation.

Bottom Line: PEPCK and G6PC were localised to fetal hepatocytes but maternal androgens had no effect on female or male fetuses.The tissue specific effects may be related to the increased expression of ESR1 (P<0.01) and AR (P<0.05) in the kidney when compared to the fetal liver.These data further highlight the fetal and sexual dimorphic effects of maternal androgenisation, an antecedent to adult disease and the plasticity of fetal development.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Reproductive Health, the University of Edinburgh, Edinburgh, United Kingdom.

ABSTRACT
Increased maternal androgen exposure during pregnancy programmes a polycystic ovary syndrome (PCOS)-like condition, with metabolic dysfunction, in adult female offspring. Other in utero exposures associated with the development of insulin resistance, such as intrauterine growth restriction and exposure to prenatal glucocorticoids, are associated with altered fetal gluconeogenesis. We therefore aimed to assess the effect of maternal androgenisation on the expression of PEPCK and G6PC in the ovine fetus. Pregnant Scottish Greyface sheep were treated with twice weekly testosterone propionate (TP; 100mg) or vehicle control from day 62 to day 102 of gestation. At day 90 and day 112 fetal plasma and liver and kidney tissue was collected for analysis. PEPCK and G6PC expression were analysed by quantitative RT-PCR, immunohistochemistry and western blotting. PEPCK and G6PC were localised to fetal hepatocytes but maternal androgens had no effect on female or male fetuses. PEPCK and G6PC were also localised to the renal tubules and renal PEPCK (P<0.01) and G6PC (P = 0.057) were lower in females after prenatal androgenisation with no change in male fetuses. These tissue and sex specific observations could not be explained by alterations in fetal insulin or cortisol. The sexual dimorphism may be related to the increase in circulating estrogen (P<0.01) and testosterone (P<0.001) in females but not males. The tissue specific effects may be related to the increased expression of ESR1 (P<0.01) and AR (P<0.05) in the kidney when compared to the fetal liver. After discontinuation of maternal androgenisation female fetal kidney PEPCK expression normalised. These data further highlight the fetal and sexual dimorphic effects of maternal androgenisation, an antecedent to adult disease and the plasticity of fetal development.

No MeSH data available.


Related in: MedlinePlus