The primary goal of this project is to elucidate the cross-talk between leptin and 17-estradiol signaling in kisspeptin neurons. Congenital leptin deficiency and/or loss of leptin function due to mutations in leptin can cause obesity and hypogonadotropic hypogonadism. Hypothalamic hypogonadism and its associated disturbances can be reversed by administration of leptin. Leptin signals via its cognate receptors, leptin receptors (LRs). The long isoform (LRb) is the predominant signaling form of the receptor and is abundantly expressed in hypothalamic neurons, including arcuate proopiomelanocortin (POMC) and kisspeptin neurons, but not in gonadotropin releasing-hormone (GnRH) neurons. Therefore, the effects of leptin on GnRH neurons are thought to be mediated indirectly via neurons synapsing on GnRH neurons. Hypothalamic kisspeptin neurons play a critical role in modulating GnRH release and hence the control of reproduction. Moreover, KiSS1 mRNA is reduced in obese and infertile ob/ob mice, and the levels of Kiss1 mRNA increase after administration of leptin. Furthermore, KiSS1 mRNA and kisspeptin protein are highly regulated by 17- estradiol (E2), and recently, we have found that E2 differentially regulates arcuate kisspeptin neurons in the female guinea pig, inhibiting expression during negative feedback and augmenting expression during positive feedback. In addition, we have discovered that leptin depolarizes POMC neurons via a novel signaling pathway that is coupled to activation of canonical transient receptor potential (TRPC) channels, and kisspeptin neurons may be similarly regulated. Therefore, our current work focuses on hypothalamic arcuate kisspeptin neurons and the interaction between E2 and leptin acting through multiple signaling cascades to affect kisspeptin neuronal excitability and ultimately the reproductive cycle. Our multidisciplinary approach incorporates a unique array of cellular and molecular tools and our combined expertise (electrophysiology, molecular biology, histochemistry and whole animal physiology). Our working hypothesis is that the kisspeptin neurons are the "gate-keeper" of excitatory drive to GnRH neurons in the female, and it is the complex interaction of E2 and leptin in these neurons that control the ovulatory cycle in fed and fasted states. Therefore, our specific aims are the following: (1) To characterize the leptin signaling pathway in arcuate kisspeptin neurons in ovariectomized female guinea pigs. (2) To characterize the effects of E2 on arcuate kisspeptin neurons during positive feedback versus negative feedback. (3) To elucidate the actions of E2 on arcuate kisspeptin neurons during positive feedback in fasted versus fed guinea pigs. (4) To elucidate the effects of E2 and fasting on the expression of K-ATP channels in kisspeptin neurons. Understanding the convergence of leptin and E2 signaling in arcuate kisspeptin neurons will provide insight into the fundamental role of these hormones in conveying metabolic cues to the reproductive axis.

Public Health Relevance

Excessive exercise, eating disorders or weight loss in women can cause amenorrhea, which is characterized by low levels of serum 17-estradiol and anovulation. It is known that during negative energy balance the hormone leptin that is released from fat stores is drastically reduced and may contribute to hypothalamic amenorrhea conditions. However, leptin receptors are not expressed in hypothalamic gonadotropin releasing hormone (GnRH) neurons, which are directly responsible for the control of the ovulatory cycle, but in kisspeptin neurons that are essential for the excitatory input to GnRH neurons. Therefore, the current studies will characterize the cross-talk between leptin and 17-estradiol signaling in kisspeptin neurons in fed and fasted states. Understanding the convergence of leptin and estrogen signaling in arcuate kisspeptin neurons will provide insight into the fundamental role of these hormones in conveying metabolic cues to the reproductive axis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068098-07
Application #
8307979
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (03))
Program Officer
Hyde, James F
Project Start
2004-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$393,023
Indirect Cost
$137,813
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Nestor, Casey C; Kelly, Martin J; R√łnnekleiv, Oline K (2014) Cross-talk between reproduction and energy homeostasis: central impact of estrogens, leptin and kisspeptin signaling. Horm Mol Biol Clin Investig 17:109-28
Qiu, Jian; Zhang, Chunguang; Borgquist, Amanda et al. (2014) Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metab 19:682-93
Smith, A W; Ronnekleiv, O K; Kelly, M J (2014) Gq-mER signaling has opposite effects on hypothalamic orexigenic and anorexigenic neurons. Steroids 81:31-5
Ronnekleiv, Oline K; Kelly, Martin J (2013) Kisspeptin excitation of GnRH neurons. Adv Exp Med Biol 784:113-31
Smith, A W; Bosch, M A; Wagner, E J et al. (2013) The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17*-estradiol. Am J Physiol Endocrinol Metab 305:E632-40
Zhang, Chunguang; Ronnekleiv, Oline K; Kelly, Martin J (2013) Kisspeptin inhibits a slow afterhyperpolarization current via protein kinase C and reduces spike frequency adaptation in GnRH neurons. Am J Physiol Endocrinol Metab 304:E1237-44
Zhang, Chunguang; Bosch, Martha A; Ronnekleiv, Oline K et al. (2013) Kisspeptin activation of TRPC4 channels in female GnRH neurons requires PIP2 depletion and cSrc kinase activation. Endocrinology 154:2772-83
Kelly, Martin J; Ronnekleiv, Oline K (2013) A selective membrane estrogen receptor agonist maintains autonomic functions in hypoestrogenic states. Brain Res 1514:75-82
Lomniczi, Alejandro; Loche, Alberto; Castellano, Juan Manuel et al. (2013) Epigenetic control of female puberty. Nat Neurosci 16:281-9
Washburn, Neal; Borgquist, Amanda; Wang, Kate et al. (2013) Receptor subtypes and signal transduction mechanisms contributing to the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis. Neuroendocrinology 97:160-75

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