The long range goal of the proposed research is to elucidate the mechanisms by which 17 -estradiol (E2) signals in hypothalamic neurons to control energy homeostasis. At the core of the regulation of energy homeostasis, and hence the central feedback of insulin (and leptin), are the hypothalamic arcuate proopiomelanocortin (POMC) and neuropeptide Y/agouti related peptide (NPY/AgRP) neurons. These neurons form a reciprocal circuit that controls energy homeostasis. We have recently discovered that both leptin and insulin depolarize POMC neurons via activation of canonical transient receptor potential (TRPC) channels, and hyperpolarize NPY/AgRP neurons via activation of KATP channels. Moreover, E2 exerts rapid effects through a putative Gq coupled membrane estrogen receptor (GqmER) that either attenuates or augments GABAB mediated inhibition to increase POMC or decrease NPY/AgRP neuronal excitability, respectively. Given the functional convergence of E2 and insulin in the hypothalamus, we propose the novel hypothesis that E2 signaling pathways act in concert with the insulin signaling pathway to upregulate POMC and downregulate NPY/AgRP neuronal excitability and gene expression in a cell specific manner. These estrogenic actions protect against the development of diet induced insulin resistance in POMC neurons. Elucidating the cell specific signaling pathways and gene expression at the single cell level will help in developing new therapies for targeting hormone actions in CNS neurons and also for countering insulin resistance in CNS neurons that leads to diabetic neuropathy and stroke. Our multidisciplinary approach incorporates a unique array of cellular, molecular and optogenetic tools and our combined expertise in electrophysiology, chemical genetics, molecular biology, histochemistry and whole animal physiology.
Our specific aims are the following: (1) To elucidate the cellular/molecular mechanisms by which insulin activates TRPC channels in POMC neurons; (2) to elucidate the mechanism by which E2 augments insulin signaling in POMC neurons; (3) to elucidate the direct inhibitory effects of POMC synaptic input to NPY/AgRP neurons using optogenetic stimulation of POMC neurons and recording of postsynaptic inhibitory responses in NPY/AgRP neurons; and (4) to elucidate the changes in insulin signaling in POMC neurons associated with diet induced insulin resistance. Women show increased risk of insulin resistance in hypoestrogenic states (e.g., with the onset of menopause), which in turn can lead to severe injury to the nervous system as seen in diabetic neuropathies and stroke. Therefore, a greater understanding of how E2 protects against insulin resistance and specifically how E2 signaling cross talks with insulin signaling wil provide unique insights and novel approaches to prevent insulin resistance in the CNS.

Public Health Relevance

The anorexigenic effects of 17 -estradiol (E2) are critical throughout the lifespan of women, who show increased risk of insulin resistance, central adiposity and cardiovascular disease with the onset of menopause. Insulin resistance, which is at the core of the metabolic syndrome, poses a global health threat. Neurons can develop insulin resistance that can lead to severe injury to the nervous system as seen in diabetic neuropathies and stroke. Our project will contribute significantly to our understanding of how E2 protects against insulin resistance and specifically how E2 signaling cross-talks with insulin signaling in CNS neurons, which will help to develop novel therapeutic treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038809-18
Application #
9492615
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Gnadt, James W
Project Start
1999-04-01
Project End
2019-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
18
Fiscal Year
2018
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
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
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
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
Conde, Kristie; Meza, Cecilia; Kelly, Martin J et al. (2016) Estradiol Rapidly Attenuates ORL-1 Receptor-Mediated Inhibition of Proopiomelanocortin Neurons via Gq-Coupled, Membrane-Initiated Signaling. Neuroendocrinology 103:787-805
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:
Padilla, Stephanie L; Qiu, Jian; Soden, Marta E et al. (2016) Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state. Nat Neurosci 19:734-741

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