Ursula Kaiser, M.D.  

Metabolic Influences on Neuroendocrine Control of Reproduction

Diabetes mellitus and other metabolic and nutritional disorders can result in many complications, including a major impact on reproductive maturation and fertility. We are interested in the neuroendocrine control of reproductive development and function.  The hypothalamic pathways by which gonadotropin-releasing hormone (GnRH) neurons are reactivated at puberty and by which the precise periodic pulsatile release of GnRH is regulated are closely intertwined with those that sense energy balance and regulate appetite and metabolism.  As one example, congenital leptin deficiency is associated with severe obesity as well as with hypogonadotropic hypogonadism that responds to leptin administration. Furthermore, leptin administration to women with hypothalamic amenorrhea improves reproductive function.  Similarly, many other genes implicated in hypothalamic pathways of appetite and energy metabolism are also associated with hypogonadotropic hypogonadism when deleted or mutated in patients or in animal models.  We are interested in dissecting the pathways by which central regulation of metabolism and reproduction interconnect. A recent avenue of investigation is the characterization of the functional roles of kisspeptin and neurokinin B in the regulation of GnRH release and action in the neuroendocrine regulation of reproductive function.  Studies have demonstrated that kisspeptin and its receptor are downstream of leptin, as administration of kisspeptin in leptin-deficient animal models results in recovery of gonadotropin secretion.  We are interested in mapping the neural pathways that link leptin action to kisspeptin and/or GnRH neurons. An additional area of interest is polycystic ovarian syndrome, a reproductive disorder associated with obesity and insulin resistance in which GnRH pulse frequency is increased, resulting in altered ratios of luteinizing hormone and follicle-stimulating hormone secretion and hence irregular menses, anovulation and infertility.  Treatment with insulin sensitizing agents results in improvement in these reproductive parameters.  It is expected that these studies will provide new insights into the links between energy balance and reproductive function, and lead to improved management of disorders of reproductive function

References.

1. Teles MG, Bianco SDC, Brito VN, Trarbach EB, Kuohung W, Xu S, Seminara SB, Mendonca BB, Kaiser UB*, Latronico AC*. A GPR54 activating mutation is associated with central precocious puberty.  New Engl J Med 2008;358:709-15. *, co-senior authors. PMCID: PMC2859966

2. Ciccone NA, Xu S, Lacza CT, Carroll RS, and Kaiser UB. Frequency-dependent regulation of FSHβ by pulsatile GnRH is mediated by functional antagonism of bZIP transcription factors. Mol Cell Biol 2010;30:1028-40. PMCID: PMC2815570

3. Gill JC, Wang O, Kakar S, Martinelli E, Carroll RS and Kaiser UB. Reproductive hormone-dependent and -independent contributions to developmental changes in kisspeptin in GnRH-deficient hypogonadal mice. PLoS ONE 2010;5:e11911. PMCID:
PMC2912854

4. Abreu AP, Noel SD, Xu S, Carroll RS, Latronico AC, Kaiser UB. Evidence of the importance of the first intracellular loop of prokineticin receptor 2 in receptor function. Mol Endocrinol 2012;26:1417-27. PMCID: PMC3404297

5. Gill JC, Navarro VM, Kwong C, Noel SD, Martin C, Xu S, Clifton DK, Carroll RS, Steiner RA, Kaiser UB. Increased neurokinin B (Tac2) expression in the mouse arcuate nucleus is an early marker of pubertal onset with differential sensitivity to sex steroid negative feedback than Kiss1. Endocrinology 2012;153:4883-93. PMCID: PMC3512019

6. Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC, Rodrigues T, Kochi C, Longui CA, Beckers D, de Zegher F, Montenegro LR, Mendonca BB, Carroll RS, Hirschhorn JN, Latronico AC, Kaiser UB. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med. 2013;368:2467-75. PMCID: PMC3808195

7. Navarro VM, Kaiser UB. Metabolic influences on neuroendocrine regulation of reproduction. Curr Opin Endocrinol Diabetes Obes. 2013;20(4):335-41. PMCID: PMC3898855

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