AUSTRALIA: A pill to eliminate obesity - and diabetes

From gelignite to superglue, polyethylene to Teflon coatings, Scotchguard to Silly Putty, the long history of science is littered with chance discoveries that fall under the title of 'serendipity'. And serendipitous is how Dr Michael Mathai describes his finding that a common blood pressure drug also might also cause weight loss and possibly reduce the chances of many overweight people around the world becoming diabetics.

Mathai is a senior lecturer in nutrition at Victoria University. With a $500,000 (US$336.800) grant from government agencies plus large sums from private foundations, he and a team of researchers and students were studying how a particular hormone affected blood pressure in mice.

"We were pursuing a different topic, investigating how to lower blood pressure by reducing the formation of the hormone with a drug that blocks the angiotensin converting enzyme or ACE." he says.

"After we found that normal mice lost weight if the enzyme was blocked, we obtained a special breed of mice from Paris that lacked the gene to make the enzyme and began more experiments."

Because the special mice had no angiotensin hormone in their bodies, their blood pressure was low, as was expected. But the researchers found their body weight was also lower compared with normal mice of the same age that had the hormone. They wondered if the body fat might be reduced as well.

"We had to use a special technique for imaging the body fat and, as I was working at the Howard Florey Institute, we were able to use its Magnetic Resonance Imaging machine.

"The MRI machine shows pictures where fat is in the body so you can scan through the animal and find out. We discovered the special mice had much lower fat levels in the abdomen but we couldn't measure it accurately."

This led to collaboration with researchers at the Royal Melbourne Hospital who had an imaging machine used for patients with osteoporosis to assess their bone density. But the machine also measured their fat and lean mass.

"We used the hospital's machine with our mice - scanned them and measured their bone density and their lean and fat composition. We could see the fat mass in the special mice was reduced whereas the lean mass was pretty much the same as in a normal mouse."

Dr Mathai thought the reduced fat mass must have been caused by a higher metabolic rate. The test mice were eating exactly the same amount of food as their normal cousins so the fat reduction was not simply due to lack of appetite but to find out he would need the help of other scientists.

"My PhD and honours students said we could get genetic analysis done of the muscle and fat tissue at Deakin University. This would allow us to get a handle on the gene expression of enzymes involved in fatty acid oxidation," he says.

The Deakin researchers carried out the analyses and were able to assess the muscle and fat expression of enzymes. They found that enzymes in the liver were involved and this indicated the higher metabolic rate in the mice was related specifically to the liver.

"To complete the energy cycle in the whole animal, we then went to La Trobe University where Dr Richard Weisinger, a colleague I had worked with at the Howard Florey Institute, had developed a technology for measuring metabolic rates in conscious, freely moving animals," Dr Mathai says.

In this experiment, normal mice and the ACE-free mice were put in separate "closed circuit environments" where the amount of carbon dioxide they produced could be measured. The mice were able to eat and move about while the quantity of CO2 was assessed: the results confirmed metabolism in the test mice was higher than with normal animals.

"All this information came in at different times from different places and we had to work back to build up the composite picture," Dr Mathai says. The way so many researchers were involved represented "a magnificent interplay" between the institutions, he says.

"In studying obesity, we had to be sure the differences weren't because normal mice were eating too much or that their metabolic rates weren't lower than the others - or that it was because they had a propensity to store fat rather than burn it off. We established the ACE-free mice weren't eating less but they were metabolising more energy even at rest."

He says that until now the usual way to speed up a human's metabolism is through regular exercise. But this is not always possible, particularly for people with disabilities so the researchers are now looking at a pill to do the job.

Mathai hopes to begin human trials within a year. The participants would be given an ACE inhibitor to block the function of the enzyme and boost their metabolic rates.

"If the treatment is effective, we could have a commercially viable therapy in the form of a pill within five years because all of the work has been done on proving the safety of these drugs," he says.

As a nutritionist, though, Mathai is also investigating whether certain micro-nutrients in food might also act as ACE inhibitors. If some were found to be effective, people could be advised to eat more of the foods that contained them.

Whatever the results of his research, he has one simple message: "I say this to anyone who will listen but it is absolutely true that the importance of eating a balanced diet along with daily exercise cannot be overstated."

geoff.maslen@uw-news.com