A major regulator of body composition, energy balance and food intake is leptin, an adipocytokine [1]. Leptin circulates and has direct actions in the brain [2] and skeletal muscle [3, 4] by binding to the B isoform of leptin receptor (LEPR-B). Loss of leptin signaling also leads to hypothalamic hypogonadism and infertility. There are numerous hypothalamic nuclei that are responsive to leptin and each of these nuclei has numerous types of neurons, as defined by their neurotransmitter content [5, 6]. There are numerous lines of evidence which indicate leptin responsive neurons within the arcuate nucleus affect gonadotropin release. The orexigenic neuropeptides NPY [7, 8] and AGRP [9] have been shown to inhibit LH release. There are anatomical projections of arcuate nucleus neurons from NPY/AGRP neurons and from POMC (endorphin projections) [10] neurons to the medial preoptic area containing GnRH neurons [11]. Nevertheless, the functional impact of melanocortin modulation of GnRH neurons is not well characterized. We present preliminary data to suggest that melanocortin signaling is important to sexual development and reproductive competence within the context of leptin signaling deficiencies. We propose to study the role of melanocortinergic transmission in modulating GnRH neurons and reproductive function. The goals of this proposal are to examine the functional importance of melanocortinergic transmission in mediating the effects of leptin on GnRH neuronal function and reproductive competence. We have four specific aims that address the roles of leptin-regulated neuronal cell types in the regulation of the reproductive system.
Aim 1. Determine the reproductive competence of mice with combined MC4R and LEPR deficiencies Aim 2, Determine the direct and indirect effects of melanocortins on GnRH neurons Aim 3. Determine the reproductive competence of increased melanocortinergic transmission in females with leptin receptor deficiency Aim 4. Determine the impact of restoring MC4R expression on GnRH neurons in females with combined MC4R and LEPR deficiencies

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
United States
Zip Code
Al-Safi, Zain A; Polotsky, Alex; Chosich, Justin et al. (2018) Evidence for disruption of normal circadian cortisol rhythm in women with obesity. Gynecol Endocrinol 34:336-340
Chosich, Justin; Bradford, Andrew P; Allshouse, Amanda A et al. (2017) Acute recapitulation of the hyperinsulinemia and hyperlipidemia characteristic of metabolic syndrome suppresses gonadotropins. Obesity (Silver Spring) 25:553-560
Kuokkanen, Satu; Zhu, Liyin; Pollard, Jeffrey W (2017) Xenografted tissue models for the study of human endometrial biology. Differentiation 98:62-69
Al-Safi, Zain A; Liu, Huayu; Carlson, Nichole E et al. (2016) Omega-3 Fatty Acid Supplementation Lowers Serum FSH in Normal Weight But Not Obese Women. J Clin Endocrinol Metab 101:324-33
Kuokkanen, Satu; Polotsky, Alex J; Chosich, Justin et al. (2016) Corpus luteum as a novel target of weight changes that contribute to impaired female reproductive physiology and function. Syst Biol Reprod Med 62:227-42
Wang, Yuxiang; Zhu, Liyin; Kuokkanen, Satu et al. (2015) Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17? is mediated by a PKC-ERK1/2-mTOR signaling pathway. Proc Natl Acad Sci U S A 112:E1382-91
Wooding, Kerry M; Hankin, Joseph A; Johnson, Chris A et al. (2015) Measurement of estradiol, estrone, and testosterone in postmenopausal human serum by isotope dilution liquid chromatography tandem mass spectrometry without derivatization. Steroids 96:89-94
Merhi, Zaher; Polotsky, Alex J; Bradford, Andrew P et al. (2015) Adiposity Alters Genes Important in Inflammation and Cell Cycle Division in Human Cumulus Granulosa Cell. Reprod Sci 22:1220-8
Ross, Lauren A; Polotsky, Alex J; Kucherov, Alexander et al. (2014) Profound reduction of ovarian estrogen by aromatase inhibition in obese women. Obesity (Silver Spring) 22:1464-9
Roth, Lauren W; Allshouse, Amanda A; Bradshaw-Pierce, Erica L et al. (2014) Luteal phase dynamics of follicle-stimulating and luteinizing hormones in obese and normal weight women. Clin Endocrinol (Oxf) 81:418-25

Showing the most recent 10 out of 41 publications