OBESITY kills, everyone knows that. But is it possible that we’ve been looking at the problem in the wrong way? It seems getting fatter may be part of your body’s defence against the worst effects of unhealthy eating, rather than their direct cause.

This curious insight comes at the same time as several studies distancing obesity itself from a host of diseases it has long been blamed for, including heart disease and diabetes.

Instead, these studies point the finger at excess fat in the bloodstream, either when the fat cells of obese people finally get overloaded or when lean people who can’t store a lot of fat eat too much. This seems to have a destructive effect by provoking the body’s immune response.

None of this changes the fact that too much rich food and too little exercise is bad for you. But viewing obesity as a symptom of an unhealthy diet, rather than the direct cause of disease and death, plus a better appreciation of the immune system’s reaction to fat, should radically change our understanding of what is shaping up to be one of modern society’s biggest health scourges. The findings also point to new ways to treat diabetes, heart disease and other diet-linked conditions.

In recent years, most rich countries, and some poorer ones, have seen a massive rise in so-called “metabolic syndrome”, whose symptoms can include insulin resistance, high blood cholesterol and an increased risk of diabetes, heart disease and stroke. That the syndrome goes hand in hand with obesity is well known, but exactly how all these conditions are linked is unclear.

In an attempt to determine the effects of obesity itself, diabetes researchers Roger Unger and Philipp Scherer, both at the University of Texas Southwestern Medical Center in Dallas, reviewed several recent studies of the role of fat cells in humans and mice.

In particular, the pair looked at the fates of people with a genetic condition that means they can’t make their own fat cells and mice genetically engineered to have low supplies of these cells and fed a diet that would make normal mice obese. They found that, despite not being obese, both tend to develop metabolic syndrome earlier on in life than their overweight, overfed counterparts.

This led Unger and Scherer to conclude that obesity protects the body from the effects of overeating by providing somewhere safe to deposit the dietary deluge of fat and sugar, which in excess is toxic to many body tissues (Trends in Endocrinology and Metabolism, DOI: 10.1016/j.tem.2010.01.009).

Only when the body’s fat cells, or adipocytes, are crammed to capacity do the problems of metabolic syndrome begin. The fully engorged adipocytes begin to die and leak their contents into the bloodstream, including saturated fatty acids such as palmitic acid. Such fats then accumulate in tissues such as the liver, pancreas and heart, where they may prompt the symptoms of metabolic syndrome.

The theory is certainly plausible, says Gökhan Hotamisligil, a diabetes and obesity researcher at the Harvard School of Public Health, Boston, who was not involved in the study. “When fat cells break, it’s like an oil tanker being hit,” he says. “It unloads this toxic cargo, almost like an oil slick.”

It also fits with what we know about age-related obesity. Leptin, a hormone produced by fat cells, directs surplus dietary fat into adipocytes and orders other cells to burn off any fat. Unger and Scherer point to rodent studies showing that leptin’s ability to do this drops off with age. The researchers conclude that fats locked safely away in adipocytes get released as we age, and that this could explain why older people who are obese are more at risk of metabolic syndrome.

By shifting the blame from fat to food, Unger and Scherer’s hypothesis also helps to explain why not all overweight people develop metabolic syndrome and some lean people do. In 2008, a study found that half of overweight and a third of obese Americans had healthy metabolic profiles, whereas a quarter of “lean” people had signs of metabolic syndrome (Archives of Internal Medicine, vol 168, p 1617).

So why is fat a problem when it breaks free of the protective adipocytes? The answer, it seems, lies with the immune system.

Preeti Kishore and her colleagues at the Albert Einstein College of Medicine in New York, injected the amount of fat typically found in a large beefburger into the blood of 30 volunteers. The volunteers’ bodies responded by producing 3 to 5 times as much as normal of a hormone called plasminogen activator inhibitor-1.

“We were surprised by the magnitude of the rise in PAI-1,” says Kishore. The researchers suggest that this increase in PAI-1 leads to metabolic syndrome. This makes sense as we already know that PAI-1 aggravates the symptoms of diabetes by making cells less responsive to insulin, which regulates blood concentrations of glucose. It is also involved in blood clotting, and blood clots can lead to strokes and heart attacks.

Kishore’s team was equally surprised to discover that PAI-1 was not produced by fat cells, as had been assumed, but immune cells called macrophages lodged in fat tissue. Fatty acids and fat cells both needed to be present to trigger the production by macrophages of PAI-1 (Science Translational Medicine, DOI: 10.1126/scitranslmed.3000292). Kishore says drugs that block PAI-1 or mop up free fatty acids might help prevent metabolic syndrome.

Meanwhile, the link between metabolic syndrome and the immune system has been further confirmed by Hotamisligil and his colleagues. When they fed mice a fat-rich diet, the animals rapidly became obese, insulin-resistant and developed other symptoms of metabolic syndrome. But mice lacking a gene called PKR stayed lean and healthy on the same diet (Cell, DOI: 10.1016/j.cell.2010.01.001).

It seems that PKR activates a “gang” of other genes responsible for inflammation, insulin resistance and metabolic dysfunction. “PKR is a high-ranking officer in this destruction,” says Hotamisligil, who adds that blocking the activation of PKR might be a way to fight both obesity and metabolic syndrome.

Unger stresses that the best way to prevent metabolic syndrome is eating less and exercising more. Still, drugs based on a greater understanding of the immune system’s role in the condition could be a useful last resort.

How dangerous are the worst foods?

That fatty foods, not body fat per se, are harmful is becoming clearer (see main story). But just how bad are the worst culprits and how do we best reduce their consumption?

Eating too much fatty food is well known to raise the risk of diabetes and heart disease. But consumption of sugary soft drinks, which has soared over recent decades (see graph), can also be harmful. That’s because insulin converts any excess sugar into fats called triglycerides, which get dumped in fat cells.

To find out how harmful these drinks are, Litsa Lambrakos of the University of California, San Francisco, and her colleagues analysed data from several major US studies. They estimate that between 1990 and 2000, sugary drinks contributed to 130,000 new cases of diabetes, 14,000 new cases of coronary heart disease, a total of 50,000 years of incapacitation due to coronary disease, and 6000 extra deaths overall. Lambrakos presented the results at a recent Cardiovascular Disease Epidemiology and Prevention conference in San Francisco. “The impact is substantial,” she says.

Lambrakos is now investigating whether a calorie tax would discourage consumption of sugary drinks, and there is already evidence that this might work.

Assessing the impact of price hikes on junk food is tough as such food has tended to become less and less expensive in real terms. However, Barry Popkin’s team at the University of North Carolina in Chapel Hill used the eating habits of 5115 young adults over 20 years to determine a relationship between the price of various foods and consumption, which they then applied to hypothetical price hikes.

They conclude that an 18 per cent tax on soda drinks would reduce the weight of the average US citizen aged 18 to 30 by 2.25 kilograms per year (Archives of Internal Medicine, vol 170, p 420). A 10 per cent increase in the cost of soda would decrease consumption by 7 per cent, while a similar tax on pizza would reduce consumption by 11 per cent.

Additional reporting by Ewen Callaway

by Andy Coghlan
New Scientist