Curing obesity involves more than telling people to eat less. The hugely overweight have reduced sensitivity to the hormone that normally stabilises fat stores – but scientists are learning more about how it works and moving closer to effective treatments.
Discussions about weight control have long since moved out of the world of women’s magazines and into science labs and government departments. As more and more people around the world become obese, the human and economic costs are taking the epidemic to crisis levels.
“Obesity is a consequence of lifestyle, over-consumption of food and environmental factors, but it’s a disease nonetheless and it is the biggest driver of chronic disease,” says Professor Tony Tiganis of the Monash Obesity and Diabetes Institute and Monash University’s Department of Biochemistry and Molecular Biology.
“Our research shows there are complex molecular mechanisms that underlie the development of obesity, and educating people – telling them to diet and exercise – is not enough,” Professor Tiganis says. “We have to come up with new ways to treat people.”
Those treatments may develop from a greater understanding of a hormone, leptin, which helps our bodies regulate their weight. Humans produce leptin in response to increasing fat deposits. It acts on the hypothalamus in the brain, sending signals to suppress appetite and increase energy expenditure: nature’s version of the classic weight-loss advice to eat less and do more.
In people of normal weight, this biological mechanism stabilises the body’s fat stores, protecting not only our ability to survive but also our reproductive fitness.
But in obese people, the hypothalamic response to leptin is diminished. As a result, the central nervous system acts as if there are low energy levels even when the body is well supplied. The normal signals to reduce the amount of food eaten, or step up energy output, simply do not happen.
Although leptin’s role is clear, Professor Tiganis says the full extent to which resistance to it influences obesity needs more investigation.
“It is believed that complex homeostatic mechanisms help maintain a set body weight in most humans,” he says. “This goes awry in people who become obese, and an elevated level of body fat is attained and defended. We are interested in the molecular mechanisms that cause changes in body weight homeostasis [equilibrium].”
In collaborative research with scientists at Harvard Medical School and the Ontario Cancer Institute, Professor Tiganis is building up knowledge about how resistance to leptin develops, recently publishing study findings in the prestigious Cell Metabolism journal.
That a high-fat diet causes elevated levels of two proteins in the brain was known already. These proteins suppress the leptin response and initiate resistance to it. Professor Tiganis’s team found that this in turn promotes a third protein, which pushes things to a point where the brain no longer responds to leptin. Thus begins an inevitable progression towards obesity.
Treatments directed at these proteins in the brain could improve leptin signalling and thereby help combat obesity.
“The next research stage will determine whether we can prevent diet-induced obesity if we delete or neutralise all three proteins from the neuronal cells,” Professor Tiganis says.
The need to develop treatments for obesity is urgent. Almost 30 per cent of European and American adults are obese, as are about 25 per cent of Australian adults. Many more are overweight. In Australia alone, the cost of obesity and related health issues is more than A$56 billion a year, according to a University of Sydney study published in the Medical Journal of Australia in March 2010.
Unless something is done, it is estimated that by 2020 more than 80 per cent of adults and almost one-third of children will be overweight or obese.
It is far from being just a question of appearance. Obesity is a significant risk factor for cardiovascular disease, type 2 diabetes and cancer – in particular liver cancer, which is the fifth most common cancer worldwide and the third most common cause of cancer death. It is also another research interest for Professor Tiganis, who has been awarded a three-year grant from the Association for International Cancer Research in the UK to examine the molecular mechanisms by which obesity drives the development of liver cancer.
“The risk of mortality from liver cancer for men who are obese is 4.5 times higher than those of normal body weight, so this is an important area for us to address,” he says.
Meanwhile, he is confident that the leptin study, which began in 2010 and is backed in Australia by a four-year National Health and Medical Research Council grant, will provide a significant weapon in the fight to combat an increasingly serious health problem.
But this is a battle that will always need to draw on a variety of factors. “Treatment must eventually represent a multi-pronged approach – drugs, diet and exercise – to prevent or manage diet-induced obesity,” he says.
The science behind the obesity epidemic
Professor Tony Tiganis and his research colleagues have found that cellular leptin resistance and obesity develop along a continuum.
Hypothalamic inflammation associated with a high-fat diet stimulates elevated levels of two proteins, called PTP1B and SOCS3, in the brain. This has the effect of suppressing the normal leptin response and initiating leptin resistance.
In turn, this leptin resistance and the associated compensatory hyperleptinemia promote the expression of a third protein called TCPTP. This protein increases resistance to the point where the brain no longer responds to leptin, and relentless progression towards morbid obesity begins.
The Monash University-led study has shown that animal models without TCPTP in their nerve cells exhibit enhanced leptin sensitivity and reduced high-fat, diet-induced weight gain. Other studies have shown that removing the first two proteins, PTP1B and SOCS3, may reduce obesity but not prevent it.
The Monash-led study further shows that removal of both PTP1B and TCPTP has a much more pronounced effect on reducing diet-induced weight gain although, again, it does not prevent it altogether.
Professor Tiganis says the study provides compelling evidence that TCPTP is a key regulator of leptin sensitivity. Treatments that inhibit all three proteins in the brain may be effective in enhancing leptin signalling and therefore combating obesity – and this is where his research is now directed.
