The long range goals of the proposed research are to elucidate the mechanism(s) by which metabolic states and 17?-estradiol (E2) regulate arcuate nucleus (ARC) kisspeptin (Kiss1) neuronal circuits that are critical for coordinating energy homeostasis and reproduction in females. It is well known that E2 is anorexigenic, and that Kiss1 neurons which are directly regulated by E2, are essential for pubertal development and adult reproductive success. However, their role in the control of energy homeostasis is less understood. We have shown that the ARC Kiss1 neurons are directly excited by leptin and insulin indicating that they may serve an important role in the control of energy homeostasis. Also, we have evidence that glutamate is released from ARC Kiss1 neurons and targets anorexigenic proopiomelanocortin (POMC) neurons and orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons. In addition, we have found that glutamate can differentially regulate POMC and NPY/AgRP neurons by acting on separate groups of metabotropic glutamate receptors (mGluRs). Moreover, we have discovered that E2 increases vesicular glutamate transporter 2 (vGluT2) mRNA in female ARC Kiss1 neurons, an indication of heightened vesicular glutamate packaging and release. We also have evidence that ARC Kiss1 neurons project to and excite AVPV/PeN Kiss1 neurons, which are important for the induction of the GnRH/LH surge. Thus, we believe that ARC Kiss1 neurons integrate metabolic hormone and steroid cues to regulate both energy homeostasis and reproduction. Therefore, we propose the novel hypothesis that the excitability of ARC Kiss1 neurons is increased in high estrogenic states thereby releasing glutamate to excite POMC neurons and inhibit NPY/AgRP neurons via group I and group II/III mGluRs, respectively, which decreases food intake. In addition, excitatory glutamatergic input to AVPV/PeN Kiss1 neurons from ARC Kiss1 neurons constitutes a critical stimulatory drive to GnRH neurons at the time of GnRH/LH surge. Our multidisciplinary approach incorporates a powerful set of cellular, molecular and optogenetic tools to address the following aims: 1) To elucidate in ARC Kiss1 neurons the effects of E2 on the mRNA expression and function of Cav3 and HCN ion channels and the expression of vGluT2 mRNA; 2) to elucidate the direct synaptic input to ARC POMC and NPY/AgRP neurons from ARC Kiss1 neurons using optogenetic stimulation in combination with whole-cell recording in E2-treated females; 3) to elucidate the direct synaptic input to AVPV/PeN Kiss1 neurons from ARC Kiss1 neurons using optogenetic stimulation and whole-cell recording in E2-treated females; 4) to elucidate the effects of high frequency optogenetic stimulation of ARC Kiss1 neurons on GnRH release and on food intake in E2-treated females. Therefore, elucidating the circuits and signaling cascades underlying the actions of E2 in the hypothalamus will provide a neurophysiological framework whereby Kiss1 neurons could coordinate reproduction with changes in energy status.

Public Health Relevance

Energy metabolism and fertility in females are inextricably linked, and 17?-estradiol (E2) is critically involved in the regulation of both, in part through its action on kisspeptin neuronal circuits. Hypoestrogenic states often lead to obesity and subsequently obesity-related adverse health conditions such as metabolic syndrome. Our project will contribute significantly to the understanding of how the hypothalamus integrates E2 and metabolic hormonal cues to regulate energy homeostasis and reproduction, which will help to develop novel therapeutic treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK068098-09A1
Application #
9174776
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Hyde, James F
Project Start
2005-03-01
Project End
2020-05-31
Budget Start
2016-07-01
Budget End
2017-05-31
Support Year
9
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Stincic, Todd L; Rønnekleiv, Oline K; Kelly, Martin J (2018) Diverse actions of estradiol on anorexigenic and orexigenic hypothalamic arcuate neurons. Horm Behav :
Qiu, Jian; Rivera, Heidi M; Bosch, Martha A et al. (2018) Estrogenic-dependent glutamatergic neurotransmission from kisspeptin neurons governs feeding circuits in females. Elife 7:
Qiu, Jian; Bosch, Martha A; Meza, Cecilia et al. (2018) Estradiol Protects Proopiomelanocortin Neurons Against Insulin Resistance. Endocrinology 159:647-664
Rivera, H M; Stincic, T L (2018) Estradiol and the control of feeding behavior. Steroids 133:44-52
Vazquez, M J; Toro, C A; Castellano, J M et al. (2018) SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression. Nat Commun 9:4194
Qiu, J; Wagner, E J; Rønnekleiv, O K et al. (2018) Insulin and leptin excite anorexigenic pro-opiomelanocortin neurones via activation of TRPC5 channels. J Neuroendocrinol 30:
Kelly, Martin J; Qiu, Jian; Rønnekleiv, Oline K (2018) TRPCing around the hypothalamus. Front Neuroendocrinol 51:116-124
Padilla, Stephanie L; Qiu, Jian; Nestor, Casey C et al. (2017) AgRP to Kiss1 neuron signaling links nutritional state and fertility. Proc Natl Acad Sci U S A 114:2413-2418
Heppner, Kristy M; Baquero, Arian F; Bennett, Camdin M et al. (2017) GLP-1R Signaling Directly Activates Arcuate Nucleus Kisspeptin Action in Brain Slices but Does not Rescue Luteinizing Hormone Inhibition in Ovariectomized Mice During Negative Energy Balance. eNeuro 4:
Qiu, Jian; Nestor, Casey C; Zhang, Chunguang et al. (2016) High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons. Elife 5:

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