Leptin action on reproductive functions is well established. Mice and humans deficient (ob/ob) or resistant (db/db) to leptin are infertile, and leptin administration to leptin-deficient subjects restore their fertility. Studies conducted in obese children deficient in leptin have supported the importance of leptin to reproductive physiology. Following leptin treatment, a gradual increase in gonadotropins and estradiol levels, enlargement of the gonads and pubertal development were observed. Leptin also blunts the fasting-induced suppression of LH secretion. In anorectic females, and those with hypothalamic amenorrhea resulting from a period of increased weight lost, leptin treatment increased pulse frequency and mean levels of LH, ovarian volume, number of dominant follicles and estradiol levels. Leptin receptors (LepR) are expressed in brain, pituitary gland and gonads. Expression of LepR in the brain of mice otherwise null for LepRs restores fertility suggesting that the brain plays a major role. However, the specific brain site where leptin acts to exert its effect in the reproductive function is still unsettled. Recently, the role played by kisspeptin (product of Kiss1 gene) and its receptor (Kiss1r) in regulating reproduction has become clear. Deletion of Kiss1 or Kiss1r genes results in hypogonadism, abnormal sexual maturation and decreased circulating levels of sex steroids and gonadotropins. A subset of Kiss1 neurons in the arcuate nucleus expresses LepR, and compared to wild types, leptin-deficient ob/ob male mice show decreased expression of Kiss1. We have recently shown that neurons in the ventral premammillary nucleus (PMV) are required for leptin action to induce LH secretion during fasting. The PMV express a dense collection of leptin responsive neurons and project to areas related to reproductive control. However, whether Kiss1 or PMV neurons relay leptin's effect on puberty initiation and coordinated reproductive control has not been directly test.
The specific aims of this proposal are designed to determine whether leptin signaling selectively in PMV neurons (Aim1) or in Kiss1 neurons (Aim2) is sufficient to mediate leptin's permissive effect in the onset of puberty and in the reproductive neuroendocrine axis. In addition, we will also assess the requirement of leptin signaling in both (PMV and Kiss1) neuronal population (Aim3) for the full rescue of the infertility phenotype of LepR null mice.
In humans, states of negative energy balance as in anorexia, cachexia and excessive exercise can all decrease gonadotropins secretion resulting in abnormal cyclicity and infertility. On the other hand, obesity and diabetes can also negatively affect fertility. The experiments proposed in this study were designed to determine the role played by hypothalamic neurons to mediate the effects of the adipocyte-derived hormone leptin in the reproductive physiology. It is hoped that our studies may open new fronts for the understanding and for further treatment of reproductive deficits caused by metabolic dysfunctions.
| Mahany, Erica B; Han, Xingfa; Borges, Beatriz C et al. (2018) Obesity and High-Fat Diet Induce Distinct Changes in Placental Gene Expression and Pregnancy Outcome. Endocrinology 159:1718-1733 |
| Venancio, Jade Cabestre; Margatho, Lisandra Oliveira; Rorato, Rodrigo et al. (2017) Short-Term High-Fat Diet Increases Leptin Activation of CART Neurons and Advances Puberty in Female Mice. Endocrinology 158:3929-3942 |
| Borges, Beatriz C; Garcia-Galiano, David; da Silveira Cruz-Machado, Sanseray et al. (2017) Obesity-Induced Infertility in Male Mice Is Associated With Disruption of Crisp4 Expression and Sperm Fertilization Capacity. Endocrinology 158:2930-2943 |
| Mohsen, Zaid; Sim, Hosung; Garcia-Galiano, David et al. (2017) Sexually dimorphic distribution of Prokr2 neurons revealed by the Prokr2-Cre mouse model. Brain Struct Funct 222:4111-4129 |
| Garcia-Galiano, David; Borges, Beatriz C; Donato Jr, Jose et al. (2017) PI3K? inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction. JCI Insight 2: |
| Borrow, A P; Stranahan, A M; Suchecki, D et al. (2016) Neuroendocrine Regulation of Anxiety: Beyond the Hypothalamic-Pituitary-Adrenal Axis. J Neuroendocrinol 28: |
| Greenwald-Yarnell, Megan L; Marsh, Courtney; Allison, Margaret B et al. (2016) ER? in Tac2 Neurons Regulates Puberty Onset in Female Mice. Endocrinology 157:1555-65 |
| Borges, Beatriz C; Garcia-Galiano, David; Rorato, Rodrigo et al. (2016) PI3K p110? subunit in leptin receptor expressing cells is required for the acute hypophagia induced by endotoxemia. Mol Metab 5:379-91 |
| Cornejo, M P; Hentges, S T; Maliqueo, M et al. (2016) Neuroendocrine Regulation of Metabolism. J Neuroendocrinol 28: |
| Torsoni, Marcio A; Borges, Beatriz C; Cote, Jessica L et al. (2016) AMPK?2 in Kiss1 Neurons Is Required for Reproductive Adaptations to Acute Metabolic Challenges in Adult Female Mice. Endocrinology 157:4803-4816 |
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