University of Dundee

Modulation of insulin sensitivity and energy balance in skeletal muscle by the endocannabinoid system

There is growing evidence that the endocannabinoid system (ECS) plays an important role in regulating energy metabolism. Indeed, specific targeting of its components such as the cannabinoid type 1 (CB1) receptor continues to provide avenues towards the development of potential treatments for obesity and related metabolic disorders, including insulin resistance and diabetes mellitus. The G protein coupled receptor, GPR55, has recently been proposed to act as a novel cannabinoid receptor, however, unlike the CB1 receptor, its pharmacology and biological function(s) remain largely unexplored1. Despite this, very recent studies have implicated a role for GPR55 in energy balance and metabolism.

In accordance with this, we demonstrate an important, yet previously unknown, role for this receptor in the modulation of key metabolic pathways in skeletal muscle, a major site of whole body glucose disposal. We have discovered that ligand-induced activation of GPR55 results in sensitisation of proximal insulin signalling events. In addition, application of known GPR55 agonists leads to increased activity and/or expression of proteins involved in promoting mitochondrial biogenesis and function.  Intriguingly, we find that GPR55 activation may also result in suppressed endocannabinoid tone through altered expression of ECS components. Collectively, our observations suggest that therapeutic modulation of peripheral GPR55 activity may provide a means for combating insulin resistance and improving metabolic status in skeletal muscle. Therefore, the main objective of this project will be to understand how direct modulation of GPR55 impacts upon signalling events regulating fuel utilisation and insulin sensitivity in skeletal muscle.