The female gonadal steroid 17β-estradiol is a pleiotropic hormone that has widespread actions not only in reproductive tissues but also has pronounced effects in the central nervous system (CNS). For over forty years, my laboratory has been studying the actions of estradiol in the CNS, specifically in hypothalamic neurons that control homeostasis and behavior using molecular, electrophysiological and more recently optogenetic techniques.
In collaboration with Drs. Oline Ronnekleiv and Tom Scanlan in the Department, we developed a novel non-steroidal compound, STX (US Patent 7,196,119) that mimics the rapid membrane actions of estradiol in hypothalamic neurons. We discovered that STX and estradiol act directly on these neurons via a G protein-coupled receptor to alter their activity. This unique membrane-associated estrogen receptor is Gq-coupled to activation of a phospholipase C-protein kinase C-protein kinase a pathway leading to desensitization of μ-opioid and GABAB receptors in POMC and Kisspeptin neurons, but sensitization of these Gαi,o-coupled receptors in NPY/AgRP neurons. We use two different experimental models. One model is the female guinea pig whose reproductive cycle mimics that of the human and therefore is ideal for doing whole-animal experiments. Another model is the transgenic female mouse in which we can target POMC-Cre, NPY/AgRP-Cre or Kisspeptin-Cre neurons to deliver viral vectors to express channel-rhodopsin for elucidating downstream synaptic targets that are responsive to gonadal and metabolic hormones. In addition, we target these neurons with CRISPR single-guide RNA viruses to selectively delete channels and transporters that are responsible for generating neuronal activity.
Estradiol is known to control feeding behavior, energy homeostasis and core body temperature, and STX appears to mimic all of these CNS actions of estrogen in female rodents. In addition, estradiol has neuroprotective effects on higher cognitive functions. Indeed, we have found that STX is as efficacious as estradiol to prevent hippocampal neuron loss following global ischemia in middle-aged rats. Furthermore, STX protects against amyloid toxicity in cultured hippocampal neurons, while sustained oral STX protects against amyloid toxicity in a mouse model of Alzheimer’s disease. Therefore, STX appears to mimic many of the "neuroprotective" actions of estradiol in the CNS.
We have recently discovered that insulin and leptin depolarize and excite POMC and Kisspeptin neurons in the arcuate nucleus via activation of canonical transient receptor potential (TRPC) channels. We are presently investigating how the Gαq-mER signaling pathway cross talks with insulin and leptin signaling to promote its actions and protect against the development of insulin resistance in obese states.
- Ph.D., 1976, University of Texas Southwestern Medical School
- Qiu, J., Bosch, M.A., Tobias, S.C., Grandy, D.K., Scanlan, T.S., Rønnekleiv, O.K. and M.J. Kelly. Rapid signaling by estrogen in hypothalamic neurons involves a novel G protein-coupled estrogen receptor that activates protein kinase C. The Journal of Neuroscience 23:9529-9540, 2003.
- Qiu, J., Bosch, M.A., Krust, A. Graham, S.M., Murphy, S.J., Korach, K.S., Chambon, P., Scanlan, T.S., Rønnekleiv, O.K. and M.J. Kelly. A G-protein-coupled estrogen receptor is involved in hypothalamic control of energy homeostasis. The Journal of Neuroscience 26:5649-5655, 2006.
- Roepke TA, Bosch MA, Rick EA, Lee B, Wagner EJ, Seidlova-Wuttke D, Wuttke W, Scanlan TS, Rønnekleiv OK, Kelly MJ. Contribution of a membrane estrogen receptor to the estrogenic regulation of body temperature and energy homeostasis. Endocrinology 151: 4926-37, 2010. PMC2946146
- Lebesgue D, Traub M, De Butte-Smith M, Hen C, Zukin RS, Kelly MJ, Etgen AM. Acute administration of non-classical estrogen receptor agonists attenuates ischemia-induced hippocampal neuron loss in middle-aged female rats. PloS ONE 5(1): e8642. PMC 2799530
- Smith A, Bosch MA, Wagner EJ, Rønnekleiv O.K. and M.J. Kelly. The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: Role in mediating the anorexigenic effects of 17β-estradiol. Am. J. Physiol. Endocrinol. Metab. 305: E632-40, 2013. PMC 3761166
- Qiu J., Zhang C., Borgquist A., Nestor C.C., Smith A.W., Bosch M.A., Ku S., Wagner E.J., Rønnekleiv O.K., and M.J. Kelly. Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metabolism, 19:682-693, 2014. PMC4116592.
- Qiu J., Nestor C.C., Zhang C., Padilla S.L., Palmiter, R.D., Kelly M.J. and O.K. Rønnekleiv. High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons. eLife 5:e16246, 2016. PMC 4995096
- Qiu, J., Bosch, M.A., Meza, C., Navarro, U.V., Nestor, C.C., Wagner, E.J., Rønnekleiv, O.K. and M.J. Kelly. Estradiol protects proopiomelanocortin neurons against insulin resistance. Endocrinology 159:647-664, 2018. PMC5774249.
- Qiu J., Rivera H.M., Bosch M.A., Padilla S.L., Stincic T.L., Palmiter R.D., Kelly M.J. and O.K. Rønnekleiv Estrogenic-dependent glutamatergic neurotransmission from kisspeptin neurons governs feeding circuits in females. eLife 7:e35656, 2018. PMC6103748
- Qiu, J., Bosch, M.A., Zhang, C., Rønnekleiv, O.K. and M.J. Kelly. Estradiol protects Neuropeptide Y/Agouti-related peptide neurons against insulin resistance in females. Neuroendocrinology 110:105-118, 2020. PMC6920578