The process of metabolizing fat and glucose to produce heat is unique to brown adipose tissue (BAT) (as well as beige adipose tissue), and is under the control of the CNS-generated sympathetic nervous system input to BAT. Although our research has defined the fundamental neural pathways through which thermal and febrile stimuli elicit changes in the sympathetic outflow to BAT, little is known about the neural circuits involve in the inhibitory influences on BAT activity, particularly those arising from sensors of metabolic signals. The findings of a consistent deficit of cold-activated BAT in obese humans and of marked improvements in glucose homeostasis upon BAT activation in models of obesity and diabetes are consistent with an over-active inhibitory regulation of BAT activity in the setting of metabolic disease. The new information from this research could contribute to reversing the detrimental inhibition of BAT activity and improve the outcomes for those with metabolic disease. In the proposed research project, we will determine the neural circuits through which viscerosensory, primarily metabolic, afferent information conveyed via the vagus and glossopharyngeal nerves produces an inhibition of the sympathetic outflow to BAT. Additionally, we seek to understand the roles of CNS regions, including the nucleus of the solitary tract, the ventrolateral medulla and the paraventricular hypothalamus, whose activation can inhibit BAT activity, in the overall inhibitory regulation of BAT activity. We propose a detailed series of in vivo electrophysiological, anatomical, neuropharmacological experiments to address four specific aims that will provide new insights into the inhibitory regulation of BAT thermogenesis.
The first aim will address the functional organization of the CNS circuits through which vagal viscerosensory afferents impinging on the NTS can inhibit BAT activity, and will include studies on the region(s) and neurotransmitter systems within the NTS, and localize the likely visceral sources and the classes of relevant physiological stimuli that mediate the potent inhibitory regulation of BAT activity mediated via vagal viscerosensory inputs. We will pursue the pathway between the secondary sensory neurons in NTS and the BAT sympathetic preganglionic neurons in the spinal cord, whose reduced discharge ultimately mediates declines in BAT activity.
The second aim will address the functional organization of the CNS circuits through which arterial chemoreceptor afferents in the glossopharyngeal nerve can drive a potent inhibition of BAT activity. In the third aim, we will characterize the role of the several populatins of neurons in the VLM in the inhibitory regulation of BAT activity, including their potential rolesin the BAT inhibitions elicited by vagal, arterial chemoreceptor and PVN activations.
The fourth aim will determine is the functional organization of the CNS circuits through which activation of PVN neurons inhibits BAT activity.

Public Health Relevance

Recent advances demonstrating significant depots of brown adipose tissue (BAT) in adult humans emphasize the importance of understanding the CNS regulation of BAT activity as it relates to the contributions of BAT thermogenesis to cold-defense, febrile responses to infection and the altered activation of BAT in the setting of metabolic disease. Elaborating the CNS pathways mediating the potent inhibitory regulation of BAT activity that can limit its function in situations of reduced availability of substrates for oxidative metabolism will help to explain the findings of a consistent deficit of cold-activated BA in obese humans and of marked improvements in glucose homeostasis upon BAT activation in models of obesity and diabetes. This new information could contribute to reversing the detrimental inhibition of BAT activity in the setting of metabolic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS091066-01
Application #
8858446
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
He, Janet
Project Start
2015-02-01
Project End
2019-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
1
Fiscal Year
2015
Total Cost
$336,875
Indirect Cost
$118,125
Name
Oregon Health and Science University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Mohammed, Mazher; Madden, Christopher J; Burchiel, Kim J et al. (2018) Preoptic area cooling increases the sympathetic outflow to brown adipose tissue and brown adipose tissue thermogenesis. Am J Physiol Regul Integr Comp Physiol 315:R609-R618
Conceição, Ellen Paula Santos da; Madden, Christopher J; Morrison, Shaun F (2017) Glycinergic inhibition of BAT sympathetic premotor neurons in rostral raphe pallidus. Am J Physiol Regul Integr Comp Physiol 312:R919-R926
Conceição, Ellen Paula Santos; Madden, Christopher J; Morrison, Shaun F (2017) Tonic inhibition of brown adipose tissue sympathetic nerve activity via muscarinic acetylcholine receptors in the rostral raphe pallidus. J Physiol 595:7495-7508
Tupone, Domenico; Cano, Georgina; Morrison, Shaun F (2017) Thermoregulatory inversion: a novel thermoregulatory paradigm. Am J Physiol Regul Integr Comp Physiol 312:R779-R786
Nakamura, Yoshiko; Yanagawa, Yuchio; Morrison, Shaun F et al. (2017) Medullary Reticular Neurons Mediate Neuropeptide Y-Induced Metabolic Inhibition and Mastication. Cell Metab 25:322-334
Madden, Christopher J; Morrison, Shaun F (2016) A high-fat diet impairs cooling-evoked brown adipose tissue activation via a vagal afferent mechanism. Am J Physiol Endocrinol Metab 311:E287-92
Morrison, Shaun F (2016) Central neural control of thermoregulation and brown adipose tissue. Auton Neurosci 196:14-24
Morrison, Shaun F (2016) Central control of body temperature. F1000Res 5:
Tupone, Domenico; Cetas, Justin S; Morrison, Shaun F (2016) Hibernation, Hypothermia and a Possible Therapeutic ""Shifted Homeostasis"" Induced by Central Activation of A1 Adenosine Receptor (A1AR). Nihon Shinkei Seishin Yakurigaku Zasshi 36:51-4
Morrison, Shaun F (2015) The thermostat concept - significant for mechanical temperature control systems, but irrelevant to mammalian thermoregulatory networks. Temperature (Austin) 2:332-3