[Obesity Discussion]

Fat Factors
By ROBIN MARANTZ HENIG
In the 30-plus years that Richard Atkinson has been studying obesity, he has always maintained that overeating doesn’t really explain it all. His epiphany came early in his career, when he was a medical fellow at U.C.L.A. engaged in a study of people who weighed more than 300 pounds and had come in for obesity surgery. “The general thought at the time was that fat people ate too much,” Atkinson, now at Virginia Commonwealth University, told me recently. “And we documented that fat people do eat too much — our subjects ate an average of 6,700 calories a day. But what was so impressive to me was the fact that not all fat people eat too much.”

One of Atkinson’s most memorable patients was Janet S., a bright, funny 25-year-old who weighed 348 pounds when she finally made her way to U.C.L.A. in 1975. In exchange for agreeing to be hospitalized for three months so scientists could study them, Janet and the other obese research subjects (30 in all) each received a free intestinal bypass. During the three months of presurgical study, the dietitian on the research team calculated how many calories it should take for a 5-foot-6-inch woman like Janet to maintain a weight of 348. They fed her exactly that many calories — no more, no less. She dutifully ate what she was told, and she gained 12 pounds in two weeks — almost a pound a day.

“I don’t think I’d ever gained that much weight that quickly,” recalled Janet, who asked me not to use her full name because she didn’t want people to know how fat she had once been. The doctors accused her of sneaking snacks into the hospital. “But I told them, ‘I’m gaining weight because you’re feeding me a tremendous amount of food!’ ”

The experience with Janet was an early inkling that traditional ideas about obesity were incomplete. Researchers and public-health officials have long understood that to maintain a given weight, energy in (calories consumed) must equal energy out (calories expended). But then they learned that genes were important, too, and that for some people, like Janet, this formula was tilted in a direction that led to weight gain. Since the discovery of the first obesity gene in 1994, scientists have found about 50 genes involved in obesity. Some of them determine how individuals lay down fat and metabolize energy stores. Others regulate how much people want to eat in the first place, how they know when they’ve had enough and how likely they are to use up calories through activities ranging from fidgeting to running marathons. People like Janet, who can get fat on very little fuel, may be genetically programmed to survive in harsher environments. When the human species got its start, it was an advantage to be efficient. Today, when food is plentiful, it is a hazard.

But even as our understanding of genes and behavior has become more refined, some cases still boggle the mind, like identical twins who eat roughly the same and yet have vastly different weights. Now a third wave of obesity researchers are looking for explanations that don’t fall into the relatively easy ones of genetics, overeating or lack of exercise. They are investigating what might seem to be the unlikeliest of culprits: the microorganisms we encounter every day.

One year ago, the idea that microbes might cause obesity gained a foothold when the Pennington Biomedical Research Center in Louisiana created the nation’s first department of viruses and obesity. It is headed by Nikhil Dhurandhar, a physician who invented the term “infectobesity” to describe the emerging field. Dhurandhar’s particular interest is in the relationship between obesity and a common virus, the adenovirus. Other scientists, led by a group of microbiologists at Washington University in St. Louis, are looking at the actions of the trillions of microbes that live in everyone’s gut, to see whether certain intestinal microbes may be making their hosts fat.

If microbes help explain even a small proportion of obesity, that could shed light on a condition that plagues millions of Americans. Today 30.5 percent of the American public is obese; that is, nearly a third of Americans have a body-mass index over 30 (which for someone of Janet’s height is 186 pounds). The Department of Health and Human Services says obesity may account for 300,000 deaths a year, making it the second-most-common preventable cause of death after cigarette smoking. It’s been linked to various diseases: diabetes, high blood pressure, heart disease, gallbladder disease, sleep apnea, osteoarthritis and some cancers. “Individuals who are obese,” the department states on its Web site, “have a 50 to 100 percent increased risk of premature death from all causes, compared to individuals with a healthy weight.”

If microbes do turn out to be relevant, at least in some cases of obesity, it could change the way the public thinks about being fat. Along with the continuing research on the genetics of obesity, the study of other biological factors could help mitigate the negative stereotypes of fat people as slothful and gluttonous and somehow less virtuous than thin people. There is, of course, the risk of overemphasizing how potent the biological forces are that make some people prone to gaining weight. Biology sets the context, and that is critical, but obesity still boils down to whether a person eats too much or exercises enough. The danger in bending too far in the direction of a biological explanation — whether that explanation is genetics, infectobesity or some theory yet to be discovered — is that it could be misinterpreted, by fat and thin alike, as saying that behavior is irrelevant.


Jeffrey Gordon, whose theory is that obesity is related to intestinal microorganisms, has never had a weight problem. He’s a rangy man, and when I met him he was dressed in a plaid shirt and clean chinos stretching over long, long legs. He wanted to be an astronaut as a kid, but he was too tall, 6-foot-2 by the time he was a teenager, and he says that back then, NASA was training only astronauts short enough to squeeze into the little space capsules of the day. Gordon has a big friendly face and curly brown hair that make him look younger than 58. He was a competitive swimmer as a child, from age 9 through his undergraduate years at Oberlin, but these days he seems more nerd than athlete: he continually makes puns, for one thing, and he alludes frequently to “Star Trek.”

“Are you ready to begin our Vulcan mind meld?” he asked when he collected me at my hotel in St. Louis, where I went to meet him and his colleagues at the Center for Genome Sciences at Washington University, which he directs. In a way, I was indeed hoping for a mind meld; I wanted to find out everything Gordon knows about the bugs in our guts, and how those bugs might contribute to human physiology — in particular, how they might make some people fat.

Of the trillions and trillions of cells in a typical human body — at least 10 times as many cells in a single individual as there are stars in the Milky Way — only about 1 in 10 is human. The other 90 percent are microbial. These microbes — a term that encompasses all forms of microscopic organisms, including bacteria, fungi, protozoa and a form of life called archaea — exist everywhere. They are found in the ears, nose, mouth, vagina, anus, as well as every inch of skin, especially the armpits, the groin and between the toes. The vast majority are in the gut, which harbors 10 trillion to 100 trillion of them. “Microbes colonize our body surfaces from the moment of our birth,” Gordon said. “They are with us throughout our lives, and at the moment of our death they consume us.”

Known collectively as the gut microflora (or microbiota, a term Gordon prefers because it derives from the Greek word bios, for “life”), these microbes have a Star Trek analogue, he says: the Borg Collective, a community of cybernetically enhanced humanoids with functions so intertwined that they operate as a single intelligence, sort of like an ant colony. In its Borglike way, the microflora assumes an extraordinary array of functions on our behalf — functions that we couldn’t manage on our own. It helps create the capillaries that line and nourish the intestines. It produces vitamins, in particular thiamine, pyroxidine and vitamin K. It provides the enzymes necessary to metabolize cholesterol and bile acid. It digests complex plant polysaccharides, the fiber found in grains, fruits and vegetables that would otherwise be indigestible.

And it helps extract calories from the food we eat and helps store those calories in fat cells for later use — which gives them, in effect, a role in determining whether our diets will make us fat or thin.

In the womb, humans are free of microbes. Colonization begins during the journey down the birth canal, which is riddled with bacteria, some of which make their way onto the newborn’s skin. From that moment on, every mother’s kiss, every swaddling blanket, carries on it more microbes, which are introduced into the baby’s system.

By about the age of 2, most of a person’s microbial community is established, and it looks much like any other person’s microbial community. But in the same way that it takes only a small percentage of our genome to make each of us unique, modest differences in our microflora may make a big difference from one person to another. It’s not clear what accounts for individual variations. Some guts may be innately more hospitable to certain microbes, either because of genetics or because of the mix of microbes already there. Most of the colonization probably happens in the first few years, which explains why the microflora fingerprints of adult twins, who shared an intimate environment (and a mother) in childhood, more closely resemble each other than they do those of their spouses, with whom they became intimate later in life.

No one yet knows whether an individual’s microflora community tends to remain stable for a lifetime, but it is known that certain environmental changes, like taking antibiotics, can alter it at least temporarily. Stop the antibiotics, and the microflora seems to bounce back — but it might not bounce back to exactly what it was before the antibiotics.

In 2004, a group of microbiologists at Stanford University led by David Relman conducted the first census of the gut microflora. It took them a year to do an analysis of just three healthy subjects, by which time they had counted 395 species of bacteria. They stopped counting before the census was complete; Relman has said the real count might be anywhere from 500 species to a few thousand.

About a year ago, Relman joined with other scientists, including Jeffrey Gordon, to begin to sequence all the genes of the human gut microflora. In early June, they published their results in Science: some 78 million base pairs in all. But even this huge number barely scratches the surface; the total number of base pairs in the gut microflora might be 100 times that. Because there are so many trillions of microbes in the gut, the vast majority of the genes that a person carries around are more microbial than human. “Humans are superorganisms,” the scientists wrote, “whose metabolism represents an amalgamation of microbial and human attributes.” They call this amalgamation — human genes plus microbial genes — the metagenome.

Gordon first began studying the connection between the microflora and obesity when he saw what happened to mice without any microbes at all. These germ-free mice, reared in sterile isolators in Gordon’s lab, had 60 percent less fat than ordinary mice. Although they ate voraciously, usually about 30 percent more food than the others, they stayed lean. Without gut microbes, they were unable to extract calories from some of the types of food they ate, which passed through their bodies without being either used or converted to fat.

When Gordon’s postdoctoral researcher Fredrik Bäckhed transplanted gut microbes from normal mice into the germ-free mice, the germ-free mice started metabolizing their food better, extracting calories efficiently and laying down fat to store for later use. Within two weeks, they were just as fat as ordinary mice. Bäckhed and Gordon found at least one mechanism that helps explain this observation. As they reported in the Proceedings of the National Academy of Sciences in 2004, some common gut bacteria, including B. theta, suppress the protein FIAF, which ordinarily prevents the body from storing fat. By suppressing FIAF, B. theta allows fat deposition to increase. A different gut microbe, M. smithii, was later found to interact with B. theta in a way that extracts additional calories from polysaccharides in the diet, further increasing the amount of fat available to be deposited after the mouse eats a meal. Mice whose guts were colonized with both B. theta and M. smithii — as usually happens in humans in the real world — were found to have about 13 percent more body fat than mice colonized by just one or the other.

Gordon likes to explain his hypothesis of what gut microbes do by talking about Cheerios. The cereal box says that a one-cup serving contains 110 calories. But it may be that not everyone will extract 110 calories from a cup of Cheerios. Some may extract more, some less, depending on the particular combination of microbes in their guts. “A diet has a certain amount of absolute energy,” he said. “But the amount that can be extracted from that diet may vary between individuals — not in a huge way, but if the energy balance is affected by just a few calories a day, over time that can make a big difference in body weight.”