Mason Inman - science journalist

17 May 2007, for Inkling  

You're not a hopeless dieter, you're a precision evolutionary famine-surviving machine

In Mauritania, morbidly obese women are considered beautiful. To symbolize wealth in a country that suffers from severe food scarcity, girls are force-fed until they’re fat.

In the land of plenty here in North America – and South America and Europe – we don’t have to try so hard. Fat just seems to come naturally. Really, really naturally.

While I contemplate this, I’m eating a big tub of ice cream. I’m not trying to make anyone jealous, but I’ve always been effortlessly thin. I exercise little and spend most of my day with my meager butt warming a desk chair. In high school I worked at an ice-cream store and gorged myself every shift. My weight barely budged. It’s like I won the genetic lottery, at least here in the U.S., where the opportunity for gluttony looms at every corner. If a famine hit in Mauritania, however, my genes could be the end of me.

The genetics of obesity, or in my case thinness, is hot science these days. Massive research projects have uncovered dozens of gene culprits in the past few years, yielding hopeful avenues for treating the growing obesity epidemic. But this plethora of targets, many still poorly understood and rarely seen, is generating more questions than answers.

The discovery of these genes fits nicely with an old theory that suggests that humans are genetically programmed for fatness in times of feast so as to withstand the always coming famines. But as the perpetual Western feast of cheap, fattening foods continues unabated and obesity-related mortality keeps climbing, those once life-saving genes might find themselves on the wrong side of evolutionary fitness. 

The Many Genes of Flabbiness
Genes contribute a surprising amount to obesity. Researchers estimate that obesity in people is about 50 to 70 percent heritable—that is, due to our genes, rather than the environment (read: “everything else”). Now, measures of heritability can be complex to interpret. But for comparison, it’s well established that height is strongly controlled by genes, and its heritability is about 75 percent.

Researchers have created mutant mice where a single mutation in the gene for the hormone leptin can make the critters balloon to sumo-like proportions. Humans with variants of this gene or of a few dozen other “obesity genes” can suffer from extreme obesity – and with it, other severe problems. Melanocortin receptor 4, one of the most-studied obesity genes, affects the body’s ability to sense insulin, apparently contributing to both obesity and diabetes. Several genes have been fingered for causing Bardet-Biedl syndrome, a rare disease that causes not only obesity, but also infertility, mental retardation and extra fingers and toes.

By homing in on people with a variety of rare diseases – such as Bardet-Biedl syndrome, along with somewhat less rare forms of obesity – researchers had hoped to uncover genes that are also at work in a lot of other obese people. But it hasn’t turned out that way. They’re turning up dozens of genes that influence weight in these small groups but don’t seem to have much to do with anyone else. But studying these genes is at least showing the variety of unexpected ways our bodies can become fat. 

Leptin, for example, was the first human obesity gene to be singled out. When we’re full, our bodies squirt out leptin, suppressing our appetites. Somewhat paradoxically, heavy people tend to have higher levels of leptin than others, so researchers think their bodies for some reason end up ignoring it. More recently, studies have found that the leptin receptor, which allows our brains to sense levels of leptin, shows mutations in some obese people, explaining their insensitivity to the signal. 

The first clear-cut, widespread obesity gene showed up in a study published last month, which scoured the DNA of nearly 40,000 people. The researchers, led by Andrew Hattersley of Peninsula Medical School in Exeter and Mark McCarthy of Oxford University, landed on a gene named FTO: 16% carried two “fat” alleles (versions) of the FTO gene, which made them pack on an extra 7 pounds on average.

This research caught headlines because it’s the first clear sign of a widespread obesity susceptibility gene. In the European population studied, around half of adults had at least one “fat” FTO allele. The new gene seems to play a role in diabetes, too – a tantalizing link, since obesity and diabetes are both rising, and the obese are at risk for developing Type II diabetes. Strangely FTO, unlike other diabetes genes, doesn’t seem to influence insulin, the hormone that regulates blood sugar levels. Instead, it was directly linked to people’s body mass index. And the authors have no clue how this gene works.

Rise of Thriftiness
But why do we have obesity genes in the first place? The most popular theory is that we have “thrifty genes,” hand-me-downs from our ancestors, who periodically faced famines and scarcity. The idea is that certain genes allow us to run more efficiently and to get by on scraps when times are lean. The flip side is that when food is a-plenty, we end up carrying around a spare tire. This obesity may or may not have hurt some of our ancestors, but the advantage of being able to survive lean times outweighed the disadvantages – so the theory says. 

It fits with what we know about certain groups of people who have faced a quick onset of extreme obesity, such as the Nauruan people of the South Pacific, says UCLA physiologist Jared Diamond (Mr. Guns, Germs and Steel to you). Over their history, Nauruans went through a couple of bottlenecks where many people died due to starvation. The first such die-off presumably occurred when the society founders made the several-weeks-long canoe trip from another island. The people who survived are probably the famine-hardy, thrifty-gene types. Diamond argues that the same can be said for most island people of the South Pacific.

This overabundance of thrifty types, paired with their recent shift from a fish-and-local-veggies diet to high-calorie processed foods, has led to a major obesity problem. As of 2004, 58% of the adult population of Nauru was obese – a level that makes the U.S., with adult obesity at only 30%, seem almost svelte.

Death to the Fatties?
Today, in a world of 44-ounce Super Big Gulps and 1,000-calorie burgers, these thrifty genes are hurting much more than they help. Researchers have projected that the average U.S. lifespan will begin to drop because of the death tolls of obesity. One 2003 study suggested that being obese might shave 20 years off your life. A 2005 National Institutes of Health study of more than 500,000 men and women aged 50 to 71 found that obese people were 2 to 3 times more likely to die over 10 years. Not only are obese people more likely to die young, they also have reduced fertility. Obese women may stop ovulating and can suffer from a fertility-crushing disorder called polycystic ovary syndrome. Overweight and obese men may suffer infertility, too, because of damaged DNA in their sperm.

Just as natural selection favored fat genes in centuries previous, the stage seems set today for evolution to weed them out. It won’t happen overnight, of course. Take the intriguing observation that mildly overweight people show lower overall mortality than normal-weight people. So perhaps, even in this modern world, a predisposition for carrying a few extra pounds might help survival.

For now, it’s likely that Joe Q. Public’s metabolism will continue to hoard calories as fast as he can dip them in ketchup and wash them down with soda. Barring the miracle discovery (and neutralization) of an all-powerful obesity gene or a silver-bullet fat drug, we’re likely to see waistlines continue to grow at home and around the world.

I still don’t know why I’m immune to getting fat. By sheer dumb luck, my ancestors must have scraped through famines on leftovers. And should famine return to the world, I guess I’m finished. But in the meantime, I need to get back to this tub of ice cream before it melts.