Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

How the central melanocortin neurons control peripheral blood glucose.  (#193)

Stephanie Simonds 1 , Michael E Cowley 1
  1. Monash University, Clayton, Vic, Australia

Diabetes rates are continuing to increase globally, and there remains an unmet need for new therapies. We also have an incomplete understanding of how blood glucose levels are regulated. In particular it has recently emerged that the brain can have a significant effect on blood glucose. Both peripheral and central mechanisms control the production of blood glucose from the liver and the uptake of glucose by muscles and other organs. The central melancortin system has been implicated in the regulation of blood glucose, but the exact mechanism by which these neurons regulate glucose levels is not yet known. In research presented here we use engineered pharmacological selective chimeric ion channels, activating and inhibiting populations of key hypothalamic arcuate neurons, including POMC, AgRP and NPY neurons in mice and examine the impact of these electrical changes on blood glucose. We have established that these neurons are differentially important in the control of blood glucose in the feed and fasted state. Activating POMC neurons causes an improved response to a glucose challenge during a glucose tolerance test (p<0.05, n=5-8). Activation of AgRP neurons causes a reduced glucose tolerant response following a glucose challenge (p<0.05, n=5-8). In fasted mice, simply activating the AgRP neurons or inhibiting the POMC neurons can increase basal blood glucose (p<0.05, n=6). We have also established that PYY can directly regulate glucose homeostasis. These actions of PYY are at least partially through the melanocortin neurons, particularly AgRP. The ability of these hypothalamic neurons to control blood glucose is altered in obesity, with differences existing between lean and obese mice. This research provides new insight into how the melanocortin system regulates blood glucose, and may provide new targets for therapies to control blood glucose.