Neural Modulation of Liver Function to Regulate Lipid and Glucose Metabolism

Abstract

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 the pancreatic hormones insulin and glucagon, which have opposite effects on blood glucose levels. In contrast, the neural messaging system is controlled via two pathways innervating the liver ‐ one sympathetic and one parasympathetic, both originating from hypothalamic areas. Previous studies have shown that electrical stimulation of these hypothalamic nuclei can lead to rapid changes in blood glucose levels. Additional studies have also shown that electrical stimulation of peripheral nerves innervating the liver can lead to changes in hepatic output, however the limitations associated with neural control of glucose and lipid levels is unclear. Here we take an interdisciplinary approach to characterizing the use of electrical stimulation to control hepatic glucose and lipid metabolism. Using electrical stimulation, we demonstrate and characterize the ability to modulate both sympathetic and parasympathetic activity to the liver, enabling modulation of the glucose clearance rate assessed via oral glucose tolerances tests. Furthermore, we demonstrate how electrical stimulation can modulate lipid metabolism as a function of frequency, amplitude, and location of stimulation.Support or Funding InformationThis work is funded by the GlaxoSmithKline Bioelectronics Initiative.