Born to be Big

On the other side of the country, Bruce Blumberg of the University of California, Irvine, had also read the 2002 Baillie-Hamilton paper. He wasn't overly impressed. "She was peddling a book with questionable claims about diets that 'detoxify' the body," he recalls. "And to find a correlation between rising levels of obesity and chemicals didn't mean much. There's a correlation between obesity and a lot of things." Nevertheless, her claim stuck in the back of his mind as he tested environmental compounds for their effects on the endocrine (hormone) system. "People were testing these compounds for all sorts of things, saying, 'Let's see what they do in my [experimental] system,' " Blumberg says. "But cells in culture are not identical to cells in the body. We had to see whether this occurred in live animals."

In 2006 he fed pregnant mice tributyltin, a disinfectant and fungicide used in marine paints, plastics production, and other products, which enters the food chain in seafood and drinking water. "The offspring were born with more fat already stored, more fat cells, and became 5 to 20 percent fatter by adulthood," Blumberg says. Genetic tests revealed how that had happened. The tributyltin activated a receptor called PPAR gamma, which acts like a switch for cells' fate: in one position it allows cells to remain fibroblasts, in another it guides them to become fat cells. (It is because the diabetes drugs Actos and Avandia activate PPAR gamma that one of their major side effects is obesity.) The effect was so strong and so reliable that Blumberg thought compounds that reprogram cells' fate like this deserved a name of their own: obesogens. As later tests would show, tributyltin is not the only obesogen that acts on the PPAR pathway, leading to more fat cells. So do some phthalates (used to make vinyl plastics, such as those used in shower curtains and, until the 1990s, plastic food wrap), bisphenol A, and perfluoroalkyl compounds (used in stain repellents and nonstick cooking surfaces).

Programming the fetus to make more fat cells leaves an enduring physiological legacy. "The more adipocytes, the fatter you are," says UCSF's Lustig. But adipocytes are more than passive storage sites. They also fine-tune appetite, producing hormones that act on the brain to make us feel hungry or sated. With more adipocytes, an animal is doubly cursed: it is hungrier more often, and the extra food it eats has more places to go—and remain.

Within a year of Blumberg's groundbreaking work, it became clear that altering cells' fate isn't the only way obesogens can act, and that exotic pollutants aren't the only potential obesogens. In 2005 Newbold began feeding newborn rats genistein, an estrogenlike compound found in soy, at doses like those in soy milk and soy formula. By the age of 3 or 4 months, the rats had higher stores of fat and a noticeable increase in body weight. And once again, mice fed genistein did not eat significantly more—not enough more, anyway, to account for their extra avoirdupois, suggesting that the compound threw a wrench in the workings of the body's metabolic rate. "The only way to gain weight is to take in more calories than you burn," says Blumberg. "But there are lots of variables, such as how efficiently calories are used." Someone who uses calories very efficiently, and burns fewer to stay warm, has more left over to turn into fat. "One of the messages of the obesogens research is that prenatal exposure can reprogram metabolism so that you are predisposed to become fat," says Blumberg.

The jury is still out on whether soy programs babies to be overweight—some studies find that it does, other studies that it doesn't—but Newbold didn't want her new grandchild to be a guinea pig in this unintentional experiment. When her daughter mentioned that she was planning to feed the baby soy formula, as about 20 percent of American mothers do, Newbold said she would cover the cost of a year's worth of regular formula if her daughter would change her mind. (She did.) As a scientist rather than a grandmother, however, Newbold hedged her bets. "Whether our results can be extrapolated to humans," she said in 2005, "remains to be determined."

Another challenge to the simplistic calories-in/calories-out model came just this month. The time of day when mice eat, scientists reported, can greatly affect weight gain. Mice fed a high-fat diet during their normal sleeping hours gained more than twice as much weight as mice eating the same type and amount of food during their normal waking hours, Fred Turek of Northwestern University and colleagues reported in the journal Obesity. And just as Newbold found, the two groups did not differ enough in caloric intake or activity levels to account for the difference in weight gain. Turek suspects that one possible cause of the difference is the disruption in the animals' circadian rhythms. Genes that govern our daily cycle of sleeping and waking "also regulate at least 10 percent of the other genes in our cells, including metabolic genes," says Turek. "Mess up the cellular clock and you may mess up metabolic rate." That would account for why the mice that ate when they should have slept gained more weight: the disruption in their clock genes lowered their metabolic rate, so they burned fewer calories to keep their body running. Studies in people have linked eating at odd times with weight gain, too.

Mice are all well and good, but many a theory has imploded when results in lab animals failed to show up in people. Unfortunately, that is not the case with obesogens. In 2005 scientists in Spain reported that the more pesticides children were exposed to as fetuses, the greater their risk of being overweight as toddlers. And last January scientists in Belgium found that children exposed to higher levels of PCBs and DDE (the breakdown product of the pesticide DDT) before birth were fatter than those exposed to lower levels. Neither study proves causation, but they "support the findings in experimental animals," says Newbold. They "show a link between exposure to environmental chemicals … and the development of obesity."

Given the ubiquity of obesogens, traces of which are found in the blood or tissue of virtually every American, why isn't everyone overweight? For now, all scientists can say is that even a slight variation in the amounts and timing of exposures might matter, as could individual differences in physiology. "Even in genetically identical mice," notes Blumberg, "you get a range of reactions to the same chemical exposure." More problematic is the question of how to deal with this cause of obesity. If obesogens have converted more precursor cells into fat cells, or have given you a "thrifty" metabolism that husbands calories like a famine victim, you face an uphill climb. "It doesn't mean you can't work out like a demon and strictly control what you eat," says Blumberg, "but you have to work at it that much harder." He and others are quick to add that obesogens do not account for all cases of obesity, especially in adults. "I'd like to avoid the simplistic story that chemicals make you fat," says Blumberg. For instance, someone who was slim throughout adolescence and then packed on pounds in adulthood probably cannot blame it on exposure to obesogens prenatally or in infancy: if that were the cause, the extra fat cells and lower metabolic rate that obesogens cause would have shown themselves in childhood chubbiness.