Leptin action on reproductive functions is well established. Mice deficient (ob/ob) or resistant (db/db) to leptin are infertile, and leptin administration to ob/ob mice, but not weight loss alone, restores their fertility. Studies conducted in obese children deficient in leptin have supported the importance of leptin to fertility. 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 and fertility. 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 db/db mice or mice otherwise null for LepRs restores fertility completely in males and partially in females, suggesting that the brain plays a major role. We have found that re-expression of LepR selectively in the ventral premammillary nucleus (PMV) induce puberty, sexual maturation and improve fertility. It has been clearly demonstrated that the long isoform of LepRs mediates cell signaling via the JAK family of tyrosine kinases and subsequent phosphorylation of STAT3. Deletion of LepR-mediated STAT3 signaling (LRbS1138 s/s) recapitulates the db/db metabolic phenotype, producing hyperphagic obesity and diabetes. Notably however, whereas db/db mice are infertile, LRbS1138 s/s mice are fertile, suggesting that the effects of leptin to regulate reproduction are exerted by JAK/STAT3-independent signaling pathways. Recently, special attention has focused on the role of phosphatidylinositol 3-kinase (PI3K) signaling pathways as mediator of leptin effects in hypothalamic neurons Therefore, we hypothesize that PI3K signaling in the PMV is required for the leptin effect on puberty and coordinated reproductive control. The studies offered in this application are designed to directly test components of this model.

Public Health Relevance

The experiments proposed in this study were designed to investigate the role played by the phosphatidylinositol 3-kinase (PI3K) signaling pathways mediating leptin action on reproduction. These studies were proposed to better understand the role of the adipocyte-derived hormone leptin in reproductive control. Our main objective is to add knowledge on how the brain integrates nutritional cues to regulate many parameters of the female reproductive physiology. 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. Obesity and diabetes can also negatively affect fertility. Thus, it is hoped that our studies may open new fronts for the understanding and for further treatment of reproductive deficits caused by metabolic dysfunctions.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD061539-06
Application #
8512759
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$289,911
Indirect Cost
$103,473
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Frazao, Renata; Dungan Lemko, Heather M; da Silva, Regina P et al. (2014) Estradiol modulates Kiss1 neuronal response to ghrelin. Am J Physiol Endocrinol Metab 306:E606-14
Bellefontaine, Nicole; Elias, Carol F (2014) Minireview: Metabolic control of the reproductive physiology: insights from genetic mouse models. Horm Behav 66:7-14
Cavalcante, Judney Cley; Bittencourt, Jackson Cioni; Elias, Carol Fuzeti (2014) Distribution of the neuronal inputs to the ventral premammillary nucleus of male and female rats. Brain Res 1582:77-90
Pedroso, João A B; Buonfiglio, Daniella C; Cardinali, Lais I et al. (2014) Inactivation of SOCS3 in leptin receptor-expressing cells protects mice from diet-induced insulin resistance but does not prevent obesity. Mol Metab 3:608-18
Elias, Carol F (2014) A critical view of the use of genetic tools to unveil neural circuits: the case of leptin action in reproduction. Am J Physiol Regul Integr Comp Physiol 306:R1-9
Ratra, Dhirender V; Elias, Carol F (2014) Chemical identity of hypothalamic neurons engaged by leptin in reproductive control. J Chem Neuroanat 61-62:233-8
Garcia-Galiano, David; Allen, Susan J; Elias, Carol F (2014) Role of the adipocyte-derived hormone leptin in reproductive control. Horm Mol Biol Clin Investig 19:141-9
Hill, Jennifer W; Alreja, Meenakshi; Elias, Carol F (2013) From precocious puberty to infertility: metabolic control of the reproductive function. Front Endocrinol (Lausanne) 4:43
Frazao, Renata; Cravo, Roberta M; Donato Jr, Jose et al. (2013) Shift in Kiss1 cell activity requires estrogen receptor *. J Neurosci 33:2807-20
Elias, Carol F; Purohit, Darshana (2013) Leptin signaling and circuits in puberty and fertility. Cell Mol Life Sci 70:841-62

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