It is not just what is in today’s diet but the way it interacts that may explain the obesity epidemic of the past 20 years. Deborah Smith reports.
THE aesthetic differences between fat lodged on the bum and the gut are on view to all, but now these two scourges of modern life are under detailed scrutiny by obesity researchers in Sydney.
Samples of the different kinds of fat have been collected from people having surgery. "And we’re doing very sophisticated genetic tests to find out what distinguishes one from the other," says Professor David James, of the Garvan Institute of Medical Research.
In Melbourne some hedonistic mice have been living a life of luxury. "We give them rat food with condensed milk and lard. They like that," says Professor Margaret Morris, who recently moved to the University of NSW. "And they get noodles with fat added, and meat pies and cake."
Not surprisingly these big eaters put on a lot of weight, and their blood tests are a worry. "They look biochemically a lot like obese humans," Morris says.
By comparison, some of their rodent cousins in Sydney can smirk. They also eat as much of a high-fat diet as they like, but because they have had one gene switched off they do not put on any extra weight and their blood test results are terrific. These so-called hot genetically modified mice stay lean by burning off the extra energy they eat.
It is easy to simply blame gluttony and sloth for the alarming rise in obesity. But these three pieces of research are part of a growing scientific attempt to dig deeper, to try to understand the complex interplay of factors that lead some to get fat while others stay thin, in a world that promotes overeating and discourages activity.
Many people do need to exercise more and consume less, and this is the overriding health message, James says. "But it’s not the whole story."
The research could eventually lead to pills that curb appetite, drugs that mimic the effects of exercise or even a way to treat the obesity problem at its source, by blocking the formation of new fat cells.
"Ideally we shouldn’t need to be even thinking about drugs for obesity, but we know that is not the situation," says Professor John Prins, of the University of Queensland.
Maintaining a healthy weight can require a lifetime of effort for many, when modern life is busy, jobs are sedentary, and tasty, fattening food is plentiful. "Humans have evolved to be extremely good at getting fat," he says.
The studies in animals could also reveal new explanations for why obesity has soared in the past 20 years. Some overseas scientists controversially claim an infectious virus that increases fatness is partly to blame.
Professor Joe Proietto, of the University of Melbourne, says a different, worrying possibility is that some ingredient in the modern diet is interacting with children’s genes, switching them on or off, so they not only get fat but their bodies then defend their new weight. "It is a very important question," he says.
Until a decade ago the science of obesity was a research backwater. Many people still, for example, mistakenly think the number of fat cells a person has is fixed in childhood, dooming them to be a doughnut or a pretzel.
However, Prins’s team has shown that fat cells can die. New ones can also form. This turnover of fat cells raises the possibility of developing a treatment that alters the number of cells a person has, he says. "It’s a strategy that had not hitherto been thought about."
His team has already discovered a protein in the body that causes fat cells to multiply. The researchers have also recently shown in the laboratory that drugs that block the action of the protein, known as FGF-1, stop new human fat cells from forming.
Not all fat is equal, and the fat that builds up around the abdomen is more of a health risk than the flab that pads out the thighs and buttocks. James’s team at the Garvan Institute is using DNA technology to see if there is any difference in the genes that are switched on and off in both types off fat.
They also want to test whether it is the nature of the fat itself or its position in the body that is the main problem. "We’re going to transplant fat from the gut to the bum in mice … and see if they are more likely to get diabetes," James says.
Studies of identical twins raised in different environments have led to estimates that genes account for about 50 per cent of weight change in adults. Other experiments show that when people are overfed the same amount, some put on weight, others do not.
"All this line of evidence suggests you need to have a genetic predisposition for our modern environment to induce obesity," Proietto says.
One of the first obesity genes discovered produces leptin, a hormone made by fat cells that suppresses appetite. Two English children with mutations in the gene were "grossly obese and perpetually hungry", Proietto says.
After taking leptin they shrank to a normal weight, and five years ago there was great hope this might be a treatment for many obese people. It was not. This genetic mutation is rare, and most overweight people, in fact, produce so much leptin they become resistant to its appetite-limiting effects.
A number of other obesity genes has been found but many more are expected to contribute to bodyweight regulation. Since 20 years is too short a time for our genes to have changed, however, the recent epidemic of obesity must be due to environmental changes including inactivity and overeating.
Proietto is concerned by American research on rats that are genetically prone to obesity. When fed a healthy diet all their lives these rats did not get fat, but on a high-energy diet they quickly stacked on the weight.
After putting the previously fattened rats on a strict diet so they lost weight, the researchers put them on a healthy diet. Instead of remaining lean, however, "they ate and ate until they went back to being obese", he says. "The high-energy diet at the beginning of their lives triggered some genes that then made these animals defend their new weight."
He speculates something in our modern diet, such as a particular fat or sugar, may be having the same effect. "If we can identify these triggers … we could carefully try to avoid feeding them to our kids."
Apart from sparking research on obesity, the discovery of leptin was important because it confirmed the importance of the brain in regulation of weight. This is where Morris’s cake-eating mice come in. "We feed them junk and then look at their brains."
Her team is exploring the brain mechanisms involved in hunger and satiety and the changes that occur during the development of obesity, as the animals gorge on their high-fat diet. "We think there is some reward system operating where desire for food is outstripping the body’s physiological response to increased fat."
How this system is affected by over-or under-nutrition in the womb or early in life could also provide an important clue to the rising childhood obesity crisis, she says. The team has found that baby rats allowed to feast on their mother’s milk, for example, quickly develop twice the fat and leptin levels of normally fed rats.
Genes also contribute to how much we jiggle and move about, and a study by the Mayo Clinic in Minnesota last year showed that the calories burnt by these spontaneous activities are far more important in keeping off the fat than had been thought.
Overweight self-declared couch potatoes were found to sit for about 2½ hours longer a day than lean couch potatoes, even after they had lost weight on a diet.
"They have a biological need to sit more," the researchers concluded, adding that if fat couch potatoes moved like the lean ones they could use up enough energy in a year to lose about 15 kilograms.
Everyone knows exercise, such as walking, is vital for maintaining a healthy bodyweight. "But the benefits extend far beyond the energy you burn [while exercising]," says Dr David Cameron-Smith of Deakin University.
He says it is easy to tell the difference in the laboratory between an active person and a sedentary one by looking at the genes in their muscles. Exercisers have more genes switched on that control enzymes that allow muscles to burn more fat.
"The human body is engineered to have physical activity. It’s the hunter-gatherer in us," Cameron-Smith says. Dropping below an activity threshold appears to switch off some genes, reducing the number of mitochondria, the energy-producing parts of the cells that readily convert fat to energy. "And if you can’t burn fat there’s only one outcome: you store it."
It takes at least three or more months of sustained activity to change this metabolism for the better, he says.
The good thing about exercise too, Prins says, is that it moves gut fat to elsewhere in the body.
People lose different amounts of weight when they are all given the same calorie-restricted diet because individuals differ in their ability to burn up energy, James says.
The hot mouse his team at the Garvan has developed reveals a possible genetic basis for this variation.
The genetically engineered mice, which lack a gene called c-Cbl, eat more than normal mice yet have less fat because they convert more food to heat.
"It’s a very exciting possibility that our hot mice are secreting a magical factor into the bloodstream that triggers their muscles to burn energy," James says. A drug that could do the same thing would not be an excuse for people to overindulge, he says. "What I think is clear is that some people are defective in this burning process, and they could benefit from this."
