title: Prenatal testosterone exposure decreases colocalization of insulin receptors in kisspeptin/neurokinin B/dynorphin and agouti-related peptide neurons of the adult ewe.
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.
authors.affiliation: Department of Neurobiology and Anatomical Sciences, The University of Mississippi Medical Center, Jackson, MS, 39232, USA.|Department of Anatomy & Cell Biology, The University of Western Ontario, London, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Cernea
authors.affiliation: Department of Neurobiology and Anatomical Sciences, The University of Mississippi Medical Center, Jackson, MS, 39232, USA.|Department of Anatomy & Cell Biology, The University of Western Ontario, London, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Phillips
authors.affiliation: Department of Obstetrics and Gynecology, Pediatrics, and Reproductive Sciences Program, The University of Michigan, Ann Arbor, MI, USA.
authors.forename: Vasantha
authors.initials: V
authors.lastname: Padmanabhan
authors.affiliation: Department of Physiology and Biophysics, The University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Lique M
authors.initials: LM
authors.lastname: Coolen
authors.affiliation: Department of Neurobiology and Anatomical Sciences, The University of Mississippi Medical Center, Jackson, MS, 39232, USA. mlehman@umc.edu.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Lehman
mesh_terms: D000375:Aging; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects; D004399:Dynorphins / Q000378:metabolism*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D059648:Kisspeptins / Q000378:metabolism*; D015287:Neurokinin B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011972:Receptor, Insulin / Q000187:drug effects* / Q000378:metabolism; D012756:Sheep; D013739:Testosterone / Q000494:pharmacology*
chemical_list: D059648:Kisspeptins; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004399:Dynorphins; D015287:Neurokinin B; D011972:Receptor, Insulin
keywords: agouti-related peptide; insulin receptor; kisspeptin; polycystic ovarian syndrome; sheep