A new way of treating obesity

 

Researchers at Trinity College are trying to find how to make cells work harder as a way to burn off fat faster and help people to lose weight. It could offer a new way to overcome obesity.

Dr Richard Porter of TCD's department of biochemistry leads a research team that is trying to understand and manipulate energy conversion inside cells. It is of "great importance for a pro-active obesity strategy," he said.

Reducing obesity is not just a matter of vanity. Many disorders are linked to obesity, including type-II diabetes and higher incidence of cardiovascular disease. The research could also reveal more about the genetic defects which account for rare forms of obesity.

A person is obese if their "body mass index" (their weight in kilograms divided by height in metres squared) is over 30. At least 8 per cent of the State's population is obese by this standard, according to a survey by the Institute of European Food Studies.

Two proteins, UCP-2 and UCP-3, are believed to regulate the efficiency of energy conversion inside cells. They are able to "uncouple" the energy-handling parts of the cell. The research in TCD aims to fully understand how these proteins work and then to see if their activity could be regulated. This would make the cell work harder, burning more fat and, the scientists hope, resulting in weight loss.

In our bodies, the energy stored in food is converted to ATP, the form of energy used in cells. Most of the ATP is made inside a component of the cell, the mitochondria, which function as the engines of a cell.

As the fat is burned, the energy is captured in the form of negatively charged electrons, which are transferred along the inner membrane of the mitochondria. The electrons combine with oxygen to form water.

At the same time, protons, positively charged particles, are pumped out of the mitochondria, creating a voltage across the mitochondrial inner membrane. The strong resulting voltage drives protons back into the mitochondria through a channel called ATP synthase, where ATP is created.

UCP-2 and UCP-3 in the mitocondrial inner membrane are believed to regulate the magnitude of this voltage and hence the efficiency of the conversion of fat to ATP by mitochondria. This is the normal process by which mitochrondria converts the energy from food into ATP.

The reason the research team believes the two proteins regulate the efficiency of energy conversion in mitochondria comes from their understanding of a specialised tissue found in new-born infants and rodents called brown fat tissue.

In brown fat, the efficiency of the conversion of fat to ATP is determined by UCP-1, a protein related in structure to UCP-2 and UCP-3. UCP-1 dissipates the voltage across the mitochondrial inner membrane. In effect, it "uncouples" the energy conversion process. In this tissue, fat is broken down and heat is generated without ATP being made.

UCP-2 is found in many of our bodies' tissues, while UCP-3 is found in human skeletal muscle.

History has shown body fat can be dramatically reduced by uncoupling mitochondria. During the second World War, French munition workers lost significant weight when they came into contact with a chemical called 2,4-dinitrophenol.

The use of the chemical as a slimming agent is now illegal, but in the 1950s it was available on prescription. Food companies were also known to have adulterated their products with the chemical.

"The chemical had a terrible reputation," Dr Porter said. "Some women developed cataracts. Others overdosed and died."

While 2,4-dinitrophenol causes indiscriminate uncoupling of mitochondria, the research in TCD will examine how the UCP-2 and UCP-3 proteins work in a natural, more subtle manner to regulate fat metabolism. The object would be to find ways of controlling energy production by acting directly on the uncoupling proteins.

Dr Porter's laboratory in Dublin is one of the few in the world which can examine how these proteins function. A better understanding may lead to the development of new drugs that can treat obesity by changing energy use inside the cell.