A Potential Hidden Factor in Why People Have So Much Trouble Losing Weight

A new study in mice points to how cell biology, not willpower, might be the root of yo-yo dieting.

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The American conventional wisdom about weight loss is simple: A calorie deficit is all that’s required to drop excess pounds, and moderating future calorie consumption is all that’s required to maintain it. To the idea’s adherents, the infinite complexity of human biology acts as one big nutritional piggy bank. Anyone who gains too much weight or loses weight and gains it back has simply failed to balance the caloric checkbook, which can be corrected by forswearing fatty food or carbs.

Endocrinologists have known for decades that the science of weight is far more complicated than calorie deficits and energy expenditures. And in 2016, the fickle complexity of weight came to broad national attention. In a study of former contestants on a season of the weight-loss reality show The Biggest Loser, scientists found that years later, the contestants not only had gained back much or all of the weight they’d lost on the show, but also had far weaker metabolisms than most people their size. The contestants’ bodies had fought for years to regain the weight, contrary to the contestants’ efforts and wishes. No one was sure why.

Along with a team of researchers, Ann Marie Schmidt, an endocrinologist at the New York University School of Medicine, has been unraveling the mystery. In a new study published today, Schmidt and her team have unlocked a molecular mechanism controlling weight gain and loss in mice: a protein that shuts down the animals’ ability to burn fat in times of bodily stress, including when dieting or overeating. This discovery might hold the key to understanding why it’s so hard for humans to lose weight, and even harder to keep it off.

In 1992, Schmidt was studying the complications of diabetes when she and her team made what she calls a startling discovery: Humans and other mammals have a protein on the surface of fat cells called the receptor for advanced glycation end products, or RAGE, which appeared to play previously unobserved roles in a host of the body’s metabolic and inflammatory responses. Eventually, it became clear that the protein was also present in nondiabetic tissues, which suggested RAGE had consequences far beyond just a few chronic diseases.

Schmidt’s latest study found an enormous difference in weight gain between two test groups: conventional mice and mice whose RAGE pathway had been deleted. The latter group gained 70 percent less weight than conventional mice, had lower glucose levels, and expended more energy while eating the same high-fat diet and doing the same amount of physical activity. The conventional mice’s bodies hit the metabolism brakes, making it impossible for them to burn as much energy as their RAGE-deleted counterparts.

Schmidt posits that RAGE might have evolved to protect mammals, including humans, when another meal might not be predictably forthcoming and the body’s ability to retain its resources would be a boon. “However, in time of plenty, when there is no shortage of nutrients, the receptor is still present and is able to continue to exert that unfortunate role of hoarding the energy and not allowing it to be expended,” she explains. It makes sense that the body would conserve resources when it detects a potential need, but it feels particularly cruel, at least in modern times, that humans might experience the same metabolic slowdown after a hearty meal.

Schmidt also theorizes that RAGE’s influence on chronic inflammation, which she had previously studied, would have been more useful to humans when our life span was much shorter. The responses would have protected short-term health, which would have been all that mattered. “These organisms didn’t live to high ages after reproduction, so it wasn’t required to survive and stay alive longer,” Schmidt says. The known side effects of RAGE, such as chronic inflammatory diseases, might have been meaningless to the well-being of humans who only lived to their 40s.

Although Schmidt cautions that the translation of her findings in mice into therapies for humans will be a long, careful process, she’s optimistic about the potential. In her new study, she found that the weight benefits of RAGE inactivity could be conferred on new animals simply by transplanting a relatively small amount of brown-fat tissue from mice that had had their RAGE pathway deleted into conventional mice. This holds promise for future treatments for patients with metabolic and chronic inflammatory disorders.

With the qualification that the study’s findings are in mice and its exact translation to humans is not yet known, Utpal Pajvani, a professor and an endocrinologist at Columbia University, expressed similar optimism about the new RAGE findings. “These data are quite interesting, and are consistent with the hypothesis that the obesity epidemic is in part due to evolutionary pressures to prevent starvation in stress,” he told me via email. “The current study adds to [Schmidt’s] impressive body of work, and suggest that methods to reduce RAGE signaling in fat may have benefit in people.”

Over the course of millennia, mammals might have developed things like RAGE to contend with their often-challenging surroundings. For humans, whose life spans have lengthened significantly in the space of only a few generations, that might be both a blessing and a curse. To meet the contemporary needs of people whose circumstances have changed at rates far quicker than evolution’s ability to keep up, findings like Schmidt’s are leading scientists toward ways to hasten the process.

For those advances to have the best chance of improving people’s lives, Schmidt cautions against the tendency to gloss over human complexity in favor of too-simple cultural beliefs, such as the idea that weight loss is just calorie deficits and willpower. “Weight loss is very, very difficult,” she says. “Only by studying the good things, the bad things, and how sometimes things that were meant to be good can go awry can we figure out the big picture and how to safely make people’s lives healthier and better.”