Natural pain killers offer a new direction in weight loss research

Researchers in the Eating Disorders Research Group at the Garvan Institute in Sydney have shown for the first time that dynorphins, the body’s natural version of morphine, play a significant role in regulating weight gain and weight loss.

Lead researcher, Dr Amanda Sainsbury-Salis says: “The dynorphins are natural brain chemicals found in what I call ‘the neurochemical soup’ around the hypothalamus - the part of the brain that regulates our appetite and body weight. To test whether dynorphins play a significant role in weight loss, we generated mice that were unable to produce any dynorphins. We found that these mice had significantly less body fat than the normal group, and they lost 15-20% more weight than normal mice while eating the same amounts of food.”

The Garvan study suggests that, for people genetically predisposed to produce higher levels of dynorphins, the body will store more fat and lose less fat than for people with lower levels, even when they are placed on the same calorie-restricted diet. This may help explain why some people find it harder to lose weight than others, despite their best efforts at dieting.

Importantly, stopping the production of dynorphin in these dynorphin ‘knockout’ mice had absolutely no effect on food intake. This has led the researchers to conclude that dynorphin deficiency can lead to weight loss by increasing the activity of some parts of the nervous system (making these mice burn off more fat) and by speeding up the passage of the food through the digestive system. Fortunately, this increased gut motility did not seem to interfere with normal nutrient absorption in the dynorphin ‘knockout’ mice.

“We believe that our body’s predisposition to store fat is influenced equally by our genetic make-up and by the environment,” says Dr Sainsbury-Salis. “It would be tempting to ask whether the levels of brain chemicals, such as dynorphin, could be lowered with drugs when trying to lose weight, but we must remember that there are at least a dozen other key players involved, as well as diet and exercise.“

One of these key brain chemicals, Neuropeptide Y, has been shown to act together with dynorphins to produce the so-called ‘famine reaction’ – the evolutionary survival mechanism that kicks in to protect us from wasting away in times of inadequate food intake. ‘The famine reaction’ promotes conservation of body fat – the fact well known to those us who ever attempted a crash diet and failed to lose much weight. Garvan researchers are now investigating whether blocking the action of both dynorphins and Neuropeptide Y could make it easier to lose weight.

“We’re well aware that blocking any of the genes involved in the ‘famine reaction’ usually causes other genes to take up the slack”, says Dr Sainsbury-Salis. “Blocking both the dynorphins and neuropeptide Y could make it easier to lose weight, but only when combined with healthy diet and regular physical activity.”

This latest research at Garvan offers a promising new direction in the development of a new type of weight loss drugs that do not rely on appetite suppression to produce weight loss. This new class of weight loss drugs could become available in about 10 years.


Note to editors

Amanda Sainsbury, Shu Lin, Keely McNamara, Katy Slack, Ronaldo Enriquez, Nicola J Lee, Dana Boey, George A Smythe, Christoph Schwarzer, Paul Baldock, Tim Karl, En-Ju D Lin, Michelle Couzens, and Herbert Herzog Dynorphin knockout reduces fat mass and increases weight loss during fasting in mice

This research is published in the July 2007 issue of Molecular Endocrinology
The accepted manuscript is available on-line at the journal’s Rapid Electronic Publication site: http://mend.endojournals.org/rep.shtml; doi:10.1210/me.2006-0367

The research was funded by Eli Lilly, NHMRC, and Diabetes Australia Research Trust.

ABOUT GARVAN
The Garvan Institute of Medical Research was founded in 1963.  Initially a research department of St Vincent's Hospital in Sydney, it is now one of Australia's largest medical research institutions with approximately 400 scientists, students and support staff. Garvan’s main research programs are: Cancer, Diabetes & Obesity, Arthritis & Immunology, Osteoporosis, and Neuroscience. The Garvan’s mission is to make significant contributions to medical science that will change the directions of science and medicine and have major impacts on human health. The outcome of Garvan’s discoveries is the development of better methods of diagnosis, treatment, and ultimately, prevention of disease.

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