Robert J. Butera, Ph.D. (Georgia Institute of Technology, School of ECE and Dept. of BME)
Chris Rozell, Ph.D. (Georgia Institute of Technology, School of ECE)
Laura O Farrell, DVM, Ph.D. (Georgia Institute of Technology, GTRC)
Arthur English, Ph.D. (Emory University, Dept. of Cell Biology)
Thomas Burkholder, Ph.D. (Georgia Institute of Technology, School of Applied Physiology)
Neural modulation of liver function to regulate lipid and glucose metabolism
Mammalian blood glucose concentrations are maintained within well-defined biological limits despite considerable fluctuations in the rate at which glucose is obtained from food and utilized by tissues. Of all homeostatic mechanisms, maintenance of blood glucose levels is finely regulated, and one in which the liver and the central nervous system play a prominent role. The liver can add or remove glucose from circulating blood in accordance with the demands of the body, which are transmitted by both hormonal and neural messaging. The hormonal messaging system is well understood, unlike the neural messaging system. Hormonal messaging is mediated by insulin and glucagon, which have opposite effects on blood glucose levels. Studies have shown that frequency-dependent electrical stimulation of peripheral nerves innervating the liver can lead to increased output of glucose by the liver. Studies have also shown that transection of the peripheral nerves innervating the liver may lead to changes in lipid and glucose metabolism. However, the magnitude and temporal scale with which these effects can be regulated remains unclear. In addition, whether electrical stimulation of peripheral nerves can lead to a decrease in blood glucose levels also remains unclear. The goal of this proposal is to investigate (1) the extent to which activity in peripheral nerves innervating the liver can be altered via electrical stimulation to regulate lipid and glucose metabolism and (2) how blood glucose levels are encoded in peripheral nerve activity for homeostatic regulation by the central nervous system. These goals will be accomplished via three specific aims: First, I will characterize the effects of electrical stimulation in a frequency-dependent manner to excite or inhibit activity in autonomic and somatic peripheral nerves. Second, I will use electrical stimulation to excite or inhibit activity in autonomic nerves innervating the liver and quantify the effects on lipid and blood glucose metabolism. Third, I will use statistical modeling methods to decode autonomic nerve activity communicated to the central nervous system and correlate nerve activity to blood glucose levels. I hypothesize that decoding liver-specific autonomic nerve activity can be used to optimize electrical stimulation, resulting in a closed-loop approach to regulate lipid and glucose metabolism via neural messaging. Together, these experiments will explore the dynamics underlying neural control of lipid and glucose metabolism.