[Obesity Discussion]

In 2004, Atkinson and Dhurandhar were ready to move to humans. All of the 50 strains of human adenoviruses cause infections that are usually mild and transient, the kind that people pass off as a cold, a stomach bug or pink eye. The symptoms are so minor that people who have been infected often don’t remember ever having been sick. Even with such an innocuous virus, it would be unethical, of course, for a scientist to infect a human deliberately just to see if the person gets fat. Human studies are, therefore, always retrospective, a hunt for antibodies that would signal the presence of an infectious agent at some point in the past. To carry out this research, Atkinson developed — and patented — a screening test to look for the presence of Ad-36 antibodies in the blood.

The scientists found 502 volunteers from Wisconsin, Florida and New York willing to be screened for antibodies, 360 of them obese and 142 of them of not obese. Of the leaner subjects, 11 percent had antibodies to Ad-36, indicating an infection at some point in the past. (Ad-36 was identified relatively recently, in 1978.) Among the obese subjects, 30 percent had antibodies— a difference large enough to suggest it was not just chance. In addition, subjects who were antibody-positive weighed significantly more than subjects who were uninfected. Those who were antibody-positive also had cholesterol and triglyceride readings that were significantly lower than people who were antibody-negative — just as in the infected chickens — a finding that held true whether or not they were obese.

Were fat people just more prone to infection? Probably not, because the scientists also screened for antibodies to two other strains of adenovirus, and there was no difference between those who were obese and those who were not. Could the differences be explained by genes instead of by viruses? Probably not, because the scientists controlled for genes in a follow-up study that involved 90 pairs of twins. In the twin study, they found 20 identical-twin pairs who were “discordant� for antibodies to Ad-36, meaning one twin had been exposed to the virus and the other twin had not. In the discordant pairs, the infected twin tended to be fatter, with an average of almost 2 percent more body fat (29.6 percent versus 27.5 percent) than the uninfected twin — even though they shared exactly the same genes.

If Ad-36 is a cause of obesity, Atkinson says, you’re more likely to catch it from a newly infected and still-contagious thin person than from someone who has already gained weight because of its effects. Exactly what the virus does to create this kind of long-term perturbation is still being investigated. In a paper published last year in The International Journal of Obesity, Atkinson and Dhurandhar, along with five of their colleagues, presented evidence for how Ad-36 might affect fat cells directly, “leading to an increased fat-cell number and increased fat-cell size.�

As for the other pathogens implicated in infectobesity — nine in all — certain viruses are known to impair the brain’s appetite-control mechanism in the hypothalamus, as happens in some cases of people becoming grossly obese after meningitis. Scientists also point to a commonality between fat cells and immune-system cells, although the exact significance of the connection is unclear. Immature fat cells, for instance, have been shown to behave like macrophages, the immune cells that engulf and destroy invading pathogens. Mature fat cells secrete hormones that stimulate the production of macrophages as well as another kind of immune-system cell, T-lymphocytes.

Another line of investigation in the field of infectobesity concerns inflammation, a corollary of infection. Obese people have higher levels of two proteins related to inflammation, C-reactive protein and interleukin-6. This may suggest that an infectious agent has set off some sort of derangement in the body’s system of fat regulation, making the infected person fat. A different interpretation is not about obesity causation but about its associated risks. Some scientists, including Jeffrey Gordon’s colleagues at Washington University, are trying to see whether the ailments of obesity (especially diabetes and high blood pressure) might be caused not by the added weight per se, but by the associated inflammation.

Infectobesity has its critics, among them Stephen Bloom, a researcher at Imperial College London. Bloom said that if he were working at a research agency, he’d give money for studies into the viral causes of obesity, just in case there’s something there. But he said he wouldn’t put the theory into a medical-school textbook just yet. His main objection, he said, is that “I don’t think we need that explanation, since we have a perfectly good other explanation.� Like Dhurandhar and Atkinson, Bloom suspects that obesity has a biological cause — but rather than turning to gut microflora or adenovirus infection for an explanation, he is partial to what he calls “the lazy-greedy gene� hypothesis, his slightly disparaging shorthand for what is more generally known as the thrifty genotype.

The thrifty-genotype hypothesis holds that there was, once upon a time, an adaptive advantage to being able to get fat. Our ancestors survived unpredictable cycles of food catastrophes by laying down fat stores when food was plentiful, and using up the stores slowly when food was scarce. The ones who did this best were the ones most likely to survive and to pass on the thrifty genotype to the next generation. But this mechanism evolved to get through a difficult winter — and we’re living now in an eternal spring. With food so readily available, thriftiness is a liability, and the ability to slow down metabolism during periods of reduced eating (a k a dieting) tends to create a fatter populace, albeit a more famine-proof one.

Bloom, by the way, does not give much credence to Dhurandhar’s analogy between the Ad-36-obesity connection and the recent history of H. pylori and ulcers — even though each started out looking like just another wacky idea. “There are so many crazy theories,� he said. “But just because one in a hundred turns out to be correct doesn’t mean all the crazy theories are correct.�


Obesity has turned out to be a daunting foe. Many of us are tethered to bodies that sabotage us in our struggle to keep from getting fat, or to slim down when we do. Microbes might be one explanation. There might be others, as outlined in June in a paper in The International Journal of Obesity listing 10 “putative contributors� to obesity, among them sleep deprivation, the increased use of psychoactive prescription drugs and the spread of air-conditioning.

But where does this leave us, exactly? Whatever the reason for any one individual’s tendency to gain weight, the only way to lose the weight is to eat less and exercise more. Behavioral interventions are all we’ve got right now. Even the supposedly biological approach to weight loss — that is, diet drugs — still works (or, more often, fails to work) by affecting eating behavior, through chemicals instead of through willpower. If it turns out that microbes are implicated in obesity, this biological approach will become more direct, in the form of an antiviral agent or a microbial supplement. But the truth is, this isn’t going to happen any time soon.

On an individual level and for the foreseeable future, if you want to lose weight, you still have to fiddle with the energy equation. Weight still boils down to the balance between how much a particular body needs to maintain a certain weight and how much it is fed. What complicates things is that in some people, for reasons still not fully understood, what their bodies need is set unfairly low. It could be genes; it could be microbes; it could be something else entirely.

Janet S. is one such person. Thirty years after her obesity surgery, 170 pounds lighter than when she started, she still needs to restrict her food intake to keep from gaining it all back.

“I definitely have to diet — damn it, I should have a pass on that, don’t you think?� said Janet, now 55, a human-resources administrator in Southern California, married and with a teenage daughter who is tall and slender. Even with the surgery, and even maintaining a weight that is borderline obese (at least according to the government definition; Janet weighs 180 pounds, plus or minus 15, meaning her body-mass index hovers around the magic number of 30), she can never enjoy food with complete and carefree abandon.

This is typical of people who have lost weight — not only a lot of weight, as Janet has, but even a little weight. According to Rudolph Leibel, an obesity researcher at Columbia University who was involved in the discovery of the first human gene implicated in obesity, if you take two nonobese people of the same weight, they will require different amounts of food depending on whether or not they were once obese. It goes in precisely the maddening direction you might expect: formerly fat people need to eat less than never-fat people to maintain exactly the same weight. In other words, a 150-pound woman who has always weighed 150 might be able to get away with eating, say, 2,500 calories a day, but a 150-pound woman who once weighed more — 20 pounds more, 200 pounds more, the exact amount doesn’t matter — would have to consume about 15 percent fewer calories to keep from regaining the weight. The change occurs as soon as the person starts reducing, Leibel said, and it “is not proportional to amount of weight lost, and persists over time.�

For many people, then, losing weight and keeping the weight off requires a constant state of hunger — and when you’re hungry, you’re miserable. You think of nothing but food every moment of the day. All morning you think about lunch, all afternoon you think about dinner, and when you’re asleep, you dream of food.

Or, as Judith Moore put it in her memoir, “Fat Girl�: “Some people daydream heroic deeds or sex scenes or tropical vacations. I daydream crab legs dipped in hot butter.� She wrote about fellow warriors who, like her, struggle to keep off the weight they worked so hard to lose. As they approach the all-you-can-eat buffet, she wrote, “they square their shoulders. They ready for combat with Virginia baked ham, sweet-potato soufflé and those puffy dinner rolls with butter and a three-layer chocolate mousse cake. Food is the enemy. Food is also the mother, the father, the warmhearted lover, the house built of redbrick that not even the wolf can blow down.�

Current public-health messages deny this harsh reality. They make losing weight sound easy, just a simple matter of doing the math and applying some willpower. A pound of fat contains 3,500 calories, government documents say, and if you cut down a week’s worth of food intake or increase exercise by a total of 3,500 calories, then, voilÃ* — you lose a pound. “To lose weight, you must use more energy than you take in,â€� states the Web site of the Office of the Surgeon General. “A difference of one 12-oz. soda (150 calories) or 30 minutes of brisk walking most days can add or subtract approximately 10 pounds to your weight each year.â€�

But if genes or viral infection or gut microflora are involved, then for some people 3,500 calories might not equal a pound of fat, and 150 fewer calories a day might not mean they’ll lose 10 pounds in a year. As scientists continue to investigate how obese people are different, we can only hope that a side benefit will be a more largehearted understanding of what it means to be fat and how hard it is to try to become, and to remain, less fat.

A more concrete benefit would be to develop ways to interfere with the action of the offending microbes. Atkinson, for one, foresees a day when Ad-36 antibody screening becomes as routine as cholesterol screening. He has a financial stake in making this happen; when he moved to Virginia two years ago, he started a company called Obetech to market his Ad-36 antibody test, for which he charges $450. But he said he has an altruistic motive as well. The people most likely to benefit from such testing, he said, are not fat people but thin people, whose infections are so recent that they haven’t yet begun to gain weight. But they are the least likely to pay to have it done without it being part of a routine checkup.

Based on animal studies, Atkinson assumes that people infected with Ad-36 have a better than even chance of becoming obese. “But if they watch their diet, and if they exercise, they can avoid it.� Further in the future, he said, there might be a way to administer antiviral drugs to infected individuals early enough to block the effect of Ad-36 on the fat cells.

Gordon, too, is hoping that his research will eventually lead to new strategies for treating obesity. It’s a long way off, he said, but it’s the beacon that keeps him and his colleagues working.

“How can you manipulate the microbial community to more broadly affect energy balance?� he asked, enumerating the research questions still to be tackled. “Can one size fit all, or can you match nutrition to the microbes in your gut?� After obese-type microflora are differentiated from lean-type, Gordon said, the next step would be what he calls “personalized nutrition� — matching diet to the digestive properties of each person’s unique microflora.

Such deliberate manipulation of the gut microflora is a long way off — years and years off, according to Gordon — but its possibility “is what this first phase of our work is underscoring, and we hope it will turn out to be an important tool in the fight against obesity.�

Robin Marantz Henig is a contributing writer to the magazine. Her last cover article was about the science of lie detection.