Trinity Researchers Reveal Mechanism of Drug Target for Potential Treatment of Obesity

Posted on: 14 November 2011

A key mechanism of naturally occurring heat production in skeletal muscle of mammals has been uncovered as a result of investigations into the basis of heat production following ingestion of ecstasy. This physiological mechanism of metabolic regulation may play a significant role in future obesity research and was discovered by a collaboration between Trinity College Dublin’s School of Biochemistry and Immunology and the School of Pharmacy and Pharmaceutical Sciences.  The discovery has been published online in the leading peer review journal Mitochondrion and builds on research previously conducted by the University of Texas.

The main site of energy conversion in our bodies is at the level of the mitochondria. Mitochondria are organelles within our cells and are similar to working mechanical engines. In the same way that engines convert chemical energy, in fuel, into kinetic energy to drive a car for instance, mitochondria convert one form of chemical energy e.g. fats, into useful energy for cells, tissues and whole body activity. However, no engine is perfectly efficient and wasted energy conversion in mechanical engines and mitochondria is manifest as heat. Thus,increasing the inefficiency of mitochondria burns more fuel (fat) while also generating more heat.

In light of the knowledge that one of the side effects of taking the psychoactive drug MDMA  (aka ecstasy) is heat production in skeletal muscle, TCD Head of Biochemistry,  Dr Richard Porter and Professor of Pharmaceutical Chemistry, Mary Meegan’s  research groups, including postgraduate students Orlagh Kelly and Yvonne McNamara, set about investigating the molecular mechanism behind the pharmacologically induced heat production.  They found that a protein, named mitochondrial uncoupling protein (UCP3), previously identified as a potential key regulator of energy conversion in skeletal muscle, was indeed switched on in mitochondria following ecstasy treatment.

Measurements of mitochondrial efficiency were made using a highly specialised piece of equipment called an Oroborus oxygraph respirometer, and the research team were able to demonstrate that UCP3 was switched on by biochemical modification following ecstasy treatment, thus uncovering the mechanism of this naturally occurring regulator of mitochondrial efficiency. The discovery is significant in that it provides a greater understanding of the molecular basis of hyperthermia in muscle and has uncovered a means to switch on UCP3 making it a potential anti-obesity/anti-type 2 diabetes target.

Commenting on the significance of the findings, Dr Porter said: “The study highlights the serendipity of science in that while investigating the damaging effects of a dangerous psychotropic drug (ecstasy), we have uncovered a potentially key physiological mechanism of metabolic regulation and have reignited the prospect of designing drugs to target this key protein (UCP3) in mammalian muscle, to burn of fat.”