Central inhibitory regulation of brown adipose thermogenesis

? DESCRIPTION (provided by applicant): 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.