Prenatal Testosterone Treatment Leads to Changes in the Morphology of KNDy Neurons, Their Inputs, and Projections to GnRH Cells in Female Sheep

Cernea, Maria; Padmanabhan, Vasantha; Goodman, Robert L.; Coolen, Lique M.; Lehman, Michael N.

doi:10.1210/en.2014-1609

Cited by 57 publications

(38 citation statements)

References 87 publications

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“…Therefore, we would speculate that contacts between IRβ‐containing axon terminals and kisspeptin or GnRH neurons may represent an additional presynaptic site of action for the effects of insulin on control of GnRH secretion. While confirmation of the IRβ‐positive close contacts we observed as bona fide synapses awaits co‐localization with markers such as synaptophysin (Cernea et al ., ), their appearance as strings of beaded varicosities (e.g., Fig. , middle panel) are consistent with that of peptidergic axons and suggest that at least some of the boutons are presynaptic in nature.…”

Section: Discussionsupporting

confidence: 72%

Prenatal testosterone exposure decreases colocalization of insulin receptors in kisspeptin/neurokinin B/dynorphin and agouti‐related peptide neurons of the adult ewe

Cernea

Phillips

Padmanabhan

et al. 2016

Eur J of Neuroscience

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Insulin serves as a link between the metabolic and reproductive systems, communicating energy availability to the hypothalamus and enabling reproductive mechanisms. Adult Suffolk ewes prenatally exposed to testosterone (T) display an array of reproductive and metabolic dysfunctions similar to those seen in women with polycystic ovarian syndrome (PCOS), including insulin resistance. Moreover, prenatal T treatment alters neuropeptide expression in KNDy (co-expressing kisspeptin, neurokinin B/dynorphin) and agouti-related peptide (AgRP) neurons in the arcuate nucleus, two populations that play key roles in the control of reproduction and metabolism, respectively. In this study, we determined whether prenatal T treatment also altered insulin receptors in KNDy and AgRP neurons, as well as in preoptic area (POA) kisspeptin, pro-opiomelanocortin (POMC), and gonadotropin-releasing hormone (GnRH) neurons of the adult sheep brain. Immunoflourescent detection of the beta subunit of insulin receptor (IRβ) revealed that KNDy, AgRP and POMC neurons, but not GnRH or POA kisspeptin neurons, colocalize IRβ in control females. Moreover, prenatal T treatment decreased the percentage of KNDy and AgRP neurons that colocalized IRβ, consistent with reduced insulin sensitivity. Administration of the anti-androgen drug, Flutamide, during prenatal T treatment, prevented the reduction in IRβ colocalization in AgRP, but not in KNDy neurons, suggesting that these effects are programmed by androgenic and estrogenic actions, respectively. These findings provide novel insight into the effects of prenatal T treatment on hypothalamic insulin sensitivity and raise the possibility that decreased insulin receptors, specifically within KNDy and AgRP neurons, may contribute to the PCOS-like phenotype of this animal model.

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Section: Discussionsupporting

confidence: 72%

Prenatal testosterone exposure decreases colocalization of insulin receptors in kisspeptin/neurokinin B/dynorphin and agouti‐related peptide neurons of the adult ewe

Cernea

Phillips

Padmanabhan

et al. 2016

Eur J of Neuroscience

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“…In our study, we noted an overall increase in Fos activation in the mid ARC associated with increased pulse frequency. This is consistent with published data demonstrating that ARC kisspeptin neurons receive "upstream" input from ARC glutamatergic neurons (Ezzat et al 2015) -although the majority of KNDy neurons themselves are glutamatergic (Cernea et al 2015;Merkley et al 2015) -potentially contributing to the GnRH pulse generator.…”

Section: Discussionsupporting

confidence: 92%

Arcuate nucleus kisspeptin response to increased nutrition in rams

Rietema

Hawken

Scott

et al. 2019

Reprod. Fertil. Dev.

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Rams respond to acute nutritional supplementation by increasing the frequency of gonadotrophin-releasing hormone (GnRH) pulses. Kisspeptin neurons may mediate the effect of environmental cues on GnRH secretion, so we tested whether the ram response to nutrition involves activation of kisspeptin neurons in the arcuate nucleus (ARC), namely kisspeptin, neurokin B, dynorphin (KNDy) neurons. Rams were given extra lupin grain with their normal ration. Blood was sampled before feeding, and continued until animals were killed for collection of brain tissue at 2 or 11h after supplementation. In supplemented rams, LH pulse frequency increased after feeding, whereas control animals showed no change. Within the caudal ARC, there were more kisspeptin neurons in supplemented rams than in controls and a higher proportion of kisspeptin cells coexpressed Fos, regardless of the time the rams were killed. There were more Fos cells in the mid-ARC and mid-dorsomedial hypothalamus of the supplemented compared with control rams. No effect of nutrition was found on kisspeptin expression in the rostral or mid-ARC, or on GnRH expression in the preoptic area. Kisspeptin neurons in the caudal ARC appear to mediate the increase in GnRH and LH production due to acute nutritional supplementation, supporting the hypothesised role of the KNDy neurons as the pulse generator for GnRH.

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“…These animals are functionally hyperandrogenic and manifest increased expression of AR at the level of the hypothalamus53, pituitary (Cordoso and Padmanabhan, unpublished) and ovary54. Cardiomyopathy has been seen in newborns with congenital adrenal hyperplasia55, a condition where the fetus is exposed to excess endogenous androgen.…”

Section: Discussionmentioning

confidence: 99%

Prenatal programming: adverse cardiac programming by gestational testosterone excess

Vyas

Hoang

Padmanabhan

et al. 2016

Sci Rep

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Adverse events during the prenatal and early postnatal period of life are associated with development of cardiovascular disease in adulthood. Prenatal exposure to excess testosterone (T) in sheep induces adverse reproductive and metabolic programming leading to polycystic ovarian syndrome, insulin resistance and hypertension in the female offspring. We hypothesized that prenatal T excess disrupts insulin signaling in the cardiac left ventricle leading to adverse cardiac programming. Left ventricular tissues were obtained from 2-year-old female sheep treated prenatally with T or oil (control) from days 30–90 of gestation. Molecular markers of insulin signaling and cardiac hypertrophy were analyzed. Prenatal T excess increased the gene expression of molecular markers involved in insulin signaling and those associated with cardiac hypertrophy and stress including insulin receptor substrate-1 (IRS-1), phosphatidyl inositol-3 kinase (PI3K), Mammalian target of rapamycin complex 1 (mTORC1), nuclear factor of activated T cells –c3 (NFATc3), and brain natriuretic peptide (BNP) compared to controls. Furthermore, prenatal T excess increased the phosphorylation of PI3K, AKT and mTOR. Myocardial disarray (multifocal) and increase in cardiomyocyte diameter was evident on histological investigation in T-treated females. These findings support adverse left ventricular remodeling by prenatal T excess.

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Prenatal Testosterone Treatment Leads to Changes in the Morphology of KNDy Neurons, Their Inputs, and Projections to GnRH Cells in Female Sheep

Cited by 57 publications

References 87 publications

Prenatal testosterone exposure decreases colocalization of insulin receptors in kisspeptin/neurokinin B/dynorphin and agouti‐related peptide neurons of the adult ewe

Prenatal testosterone exposure decreases colocalization of insulin receptors in kisspeptin/neurokinin B/dynorphin and agouti‐related peptide neurons of the adult ewe

Arcuate nucleus kisspeptin response to increased nutrition in rams

Prenatal programming: adverse cardiac programming by gestational testosterone excess

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