Maintaining an adequate supply of glucose, the brain's essential metabolic fuel, requires receptor cells that monitor brain glucose availability and engage neural circuitry capable of eliciting endocrine, autonomic and behavioral responses to restore glucose when levels fall. Our work has revealed that hindbrain catecholamine (NE/E) neurons are required for elicitation of a number of key responses to glucose deficit, including stimulation of feeding, corticosterone (CORT) and adrenal medullary secretion and suppression of reproductive responses. Understanding hindbrain glucoregulatory circuitry has been a continuing effort in our lab and is the focus of this application. Two major gaps in our knowledge of this hindbrain system will be addressed by this proposal. First, we do not understand the circuitry by which rostrally-projecting NE/E neurons mediate feeding and corticosterone responses to glucose deficit (""""""""glucoprivation""""""""). Second, although we've shown that NE/E neurons are required for elicitation and coordination of glucoregulatory responses during glucose deficit, we do not know whether E/NE neurons are themselves glucose- sensors. The proposed work will determine the contribution of NE/E innervation of the ventral tegmental (VTA) dopamine (DA) system to elicitation of appetitive feeding responses by systemic glucoprivation and determine whether this VTA innervation arises from the same NE/E neurons mediating the CORT response to glucoprivation. Experiments will utilize the retrogradely transported targeted immunotoxin, anti-dopamine beta hydroxylase saporin (DSAP) to selectively lesion NE/E neurons innervating the VTA without damaging the VTA DA neurons. The proposed work will also use gene silencing to further delineate the specific hindbrain NE/E cell groups that mediate glucoprivation-induced feeding and/or corticosterone secretion. Finally, the proposed work will examine the contribution of 5'adenosine monophosphate-activated protein kinase (AMPK), a cellular energy sensor and regulator, to the function of hindbrain NE/E neurons during glucose deficit and the possibility that these neurons are glucose sensors. Our long-term goal is to determine the potential of hindbrain NE/E neurons to serve as glucose sensors and to establish the roles of their afferent inputs and efferent outputs in the overall physiological response to glucose deficit. We believe that our work will have a significant impact on human health. Unraveling glucoregulatory circuits will enable assessment of their involvement in metabolic disorders such as Type 2 diabetes, obesity and the potentially lethal complication of insulin therapy in diabetics (known as Hypoglycemia Associated Autonomic Failure, or HAAF), in which severe reductions in glucose availability fail to trigger life-saving glucoregulatory responses.

Public Health Relevance

Glucose is the brain's essential metabolic fuel. This proposal is focused on mechanisms by which the brain protects its glucose supply and extends our previous work demonstrating the required participation of hindbrain catecholamine neurons in protective and restorative responses to glucose deficit. The proposed work will delineate the catecholamine projections that mediate two critical responses to glucose deficit, feeding and corticosterone secretion, and will examine the potential role of hindbrain catecholamine neurons as glucose sensors. Results will provide new insights into the ways in which hindbrain glucoregulatory mechanisms contribute to or are altered by obesity, diabetes and other metabolic diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Yanovski, Susan Z
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Washington State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Li, Ai-Jun; Wang, Qing; Dinh, Thu T et al. (2016) Mercaptoacetate blocks fatty acid-induced GLP-1 secretion in male rats by directly antagonizing GPR40 fatty acid receptors. Am J Physiol Regul Integr Comp Physiol 310:R724-32
Li, Ai-Jun; Wang, Qing; Davis, Hana et al. (2015) Orexin-A enhances feeding in male rats by activating hindbrain catecholamine neurons. Am J Physiol Regul Integr Comp Physiol 309:R358-67
Li, Ai-Jun; Wang, Qing; Elsarelli, Megan M et al. (2015) Hindbrain Catecholamine Neurons Activate Orexin Neurons During Systemic Glucoprivation in Male Rats. Endocrinology 156:2807-20
Li, Ai-Jun; Wang, Qing; Dinh, Thu T et al. (2014) Stimulation of feeding by three different glucose-sensing mechanisms requires hindbrain catecholamine neurons. Am J Physiol Regul Integr Comp Physiol 306:R257-64
Darling, Rebecca A; Zhao, Huan; Kinch, Dallas et al. (2014) Mercaptoacetate and fatty acids exert direct and antagonistic effects on nodose neurons via GPR40 fatty acid receptors. Am J Physiol Regul Integr Comp Physiol 307:R35-43
Wiater, Michael F; Li, Ai-Jun; Dinh, Thu T et al. (2013) Leptin-sensitive neurons in the arcuate nucleus integrate activity and temperature circadian rhythms and anticipatory responses to food restriction. Am J Physiol Regul Integr Comp Physiol 305:R949-60
Li, Ai-Jun; Wang, Qing; Dinh, Thu T et al. (2013) Hindbrain catecholamine neurons control rapid switching of metabolic substrate use during glucoprivation in male rats. Endocrinology 154:4570-9
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Li, Ai-Jun; Wiater, Michael F; Oostrom, Marjolein T et al. (2012) Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms. Am J Physiol Regul Integr Comp Physiol 302:R1313-26
Wiater, M F; Mukherjee, S; Li, A-J et al. (2011) Circadian integration of sleep-wake and feeding requires NPY receptor-expressing neurons in the mediobasal hypothalamus. Am J Physiol Regul Integr Comp Physiol 301:R1569-83

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