Prenatal testosterone exposure decreases colocalization of insulin receptors in kisspeptin/neurokinin B/dynorphin and agouti‐related peptide neurons of the adult ewe
Cernea, Maria; Phillips, Rebecca; Padmanabhan, Vasantha; Coolen, Lique M.; Lehman, Michael N.
2016-10
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Cernea, Maria; Phillips, Rebecca; Padmanabhan, Vasantha; Coolen, Lique M.; Lehman, Michael N. (2016). "Prenatal testosterone exposure decreases colocalization of insulin receptors in kisspeptin/neurokinin B/dynorphin and agouti‐related peptide neurons of the adult ewe." European Journal of Neuroscience 44(8): 2557-2568.
Abstract
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. Immunofluorescent 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 oestrogenic 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.Long‐term consequences of prenatal T treatment on insulin receptor beta (IRβ) colocalization within AgRP, POMC and KNDy neurons of the female sheep hypothalamus. Decreased IRβ colocalization within AgRP and KNDy neurons may result in decreased insulin sensitivity in these neurons and altered steroid feedback control of GnRH secretion, thereby contributing to the metabolic and reproductive disruptions seen in the PCOS‐like phenotype of this animal model.Publisher
Humana Press Wiley Periodicals, Inc.
ISSN
0953-816X 1460-9568
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