Wednesday, January 15, 2025
1/15/2025
Project Summary In 2003, two key manuscripts reported that gene mutations for the G-protein coupled receptor, kisspeptin receptor (Kiss1r), were responsible for hypogonadotropic hypogonadism (HH) 1, 2. These findings were the first to suggest that kisspeptin, a hypothalamic neuropeptide, is a critically important regulator of reproductive function. It is now known that kisspeptin neurons, specifically those co-expressing Tac2 (neurokinin B, NKB) and kappa opioid receptors (KOR), in the arcuate (ARC) nucleus (KNDy neurons) play a principal role in the stimulation of pulsatile gonadotropin-releasing hormone (GnRH) release and thus in the control of pituitary gonadotropin secretions and maintenance of fertility. The proposed studies are designed to further our understanding of the physiological roles that these neurons play in the homeostatic regulation of reproductive hormone secretions and the control of energy homeostasis. We recently demonstrated that the elimination of kisspeptin expression in KNDy neurons reduced but did not abolish pulsatile luteinizing hormone (LH) secretion. Interestingly, we detected an increase in KNDy neuron Tac2 (NKB) expression correlated with the loss of KNDy neuron kisspeptin. The proposed studies in Aim 1 will determine if NKB signaling through secondary mechanisms plays an obligatory role in controlling GnRH release in the absence of kisspeptin from KNDy neurons. We will use pharmacologic studies and genetically modified mouse models to delineate the role of NKB in mediating LH secretion in the absence of KNDy neuron kisspeptin. KNDy neurons have also been implicated in the control of feeding and energy expenditure and are a target of estradiol action. However, whether kisspeptin is directly involved in regulating metabolism and how sex steroids mediate kisspeptin action is incompletely understood. Our preliminary data demonstrate that female, but not male, KNDy cell-specific kisspeptin knockout (Kiss1KNDy KO) mice gain significantly more weight than their wild-type counterparts. It remains unknown, however, if hypothalamic kisspeptin directly modulates energy metabolism. Aim 2 will use diet-induced obesity, metabolic testing, gonadectomy, and sex steroid replacement paradigms in Kiss1KNDy KO to determine the role of KNDy neuron kisspeptin in mediating metabolic function and the effects of sex steroids on metabolism. Disorders of pulsatility contribute to reproductive disorders in humans that are associated with metabolic dysfunction. Hypogonadotropic hypogonadism is characterized by chronically insufficient gonadotropin hormone production leading to reproductive (e.g., adult-onset amenorrhea) and metabolic deficits (e.g., obesity). At another extreme, polycystic ovary syndrome (PCOS) is characterized by accelerated gonadotropin hormone production, leading to similar reproductive (e.g., oligomenorrhea, infertility) and metabolic deficits (e.g., type 2 diabetes). Our findings aim to delineate the neuroendocrine mechanisms involving neuropeptides produced in KNDy neurons that may mediate the control of reproduction hormone secretions and metabolic systems, leading to novel diagnostic and therapeutic interventions.
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