Obesity and diabetes are unusually prevalent disruptions of energy homeostatic mechanisms which have significant consequences for the health and quality of life of afflicted individuals and impose an enormous financial burden on our nation's health care system. The long-term objective of this research is to understand the central neural circuits through which the brain influences energy expenditure, a key component of energy homeostasis and body weight regulation. Treating such dysregulatiohs of energy homeostasis would be aided by an understanding of the functional organization and neurotransmitters within the central neural pathways that are activated by metabolic signals. The proposed research plan is a logical extension of the results from the initial funding period to directly test a series of specific hypotheses represented in our model of the central neural circuits through which metabolic signals, acting within the hypothalamus, influence brown adipose tissue (BAT) thermogenesis and heart rate by changing the activity of specific populations of brainstem sympathetic premotor neurons. These studies will provide, for the first time, the unique opportunity to define each of the synaptic integration sites in the pathways by which hypothalamic neurons regulate sympathetically-mediated energy expenditure. The proposed studies to elucidate the organization, function and pharmacology of the longitudinally- organized, core pathway for the metabolically-regulated sympathetic activation of BAT thermogenesis and heart rate will combine data from anatomical tracing and immunocytochemical experiments with those from studies examining the effects on sympathetic outflows from microinjection of substances into specific brain regions to guide subsequent electrophysiological recordings from single neurons at sites in the hypothalamus, pons and medullary raphe pallidus. The three specific aims will focus on the relevant anatomical connections, the evoked physiological responses and the behavior of functionally-identified neurons in (1) the dorsomedial hypothalamus, (2) the ventromedial periaqueductal gray and (3) the medial preoptic hypothalamus, respectively, to test clearly defined hypotheses on their functional roles in the activation of RPa neurons that leads to increased energy expenditure and heart rate evoked during the response to leptin or melanocortin agonist administration. Understanding the pharmacology within this pathway driving the sympathetic responses during fever could provide a foundation for developing strategies to alter sympathetically-mediated energy expenditure in support of a reduction in energy storage depots.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Sato, Sheryl M
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Oregon Health and Science University
Schools of Medicine
United States
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Morrison, Shaun F (2016) Central neural control of thermoregulation and brown adipose tissue. Auton Neurosci 196:14-24
Morrison, Shaun F; Madden, Christopher J (2014) Central nervous system regulation of brown adipose tissue. Compr Physiol 4:1677-713
Morrison, Shaun F; Madden, Christopher J; Tupone, Domenico (2014) Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab 19:741-756
Morrison, Shaun F; Madden, Christopher J; Tupone, Domenico (2012) Central control of brown adipose tissue thermogenesis. Front Endocrinol (Lausanne) 3:
Morrison, Shaun F; Nakamura, Kazuhiro (2011) Central neural pathways for thermoregulation. Front Biosci (Landmark Ed) 16:74-104
Morrison, Shaun F (2011) 2010 Carl Ludwig Distinguished Lectureship of the APS Neural Control and Autonomic Regulation Section: Central neural pathways for thermoregulatory cold defense. J Appl Physiol 110:1137-49
Madden, Christopher J; Morrison, Shaun F (2010) Endogenous activation of spinal 5-hydroxytryptamine (5-HT) receptors contributes to the thermoregulatory activation of brown adipose tissue. Am J Physiol Regul Integr Comp Physiol 298:R776-83
Cao, Wei-Hua; Madden, Christopher J; Morrison, Shaun F (2010) Inhibition of brown adipose tissue thermogenesis by neurons in the ventrolateral medulla and in the nucleus tractus solitarius. Am J Physiol Regul Integr Comp Physiol 299:R277-90
Nakamura, Kazuhiro; Morrison, Shaun F (2010) A thermosensory pathway mediating heat-defense responses. Proc Natl Acad Sci U S A 107:8848-53
Madden, C J; Morrison, S F (2009) Neurons in the paraventricular nucleus of the hypothalamus inhibit sympathetic outflow to brown adipose tissue. Am J Physiol Regul Integr Comp Physiol 296:R831-43

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