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The physiology of weight regain still baffles scientists, but surprising insights have emerged.

Why is it so hard to lose weight and keep it off? For a moment, several years ago, it looked like we had an answer. In May 2016, The New York Times ran a front-page story on the findings from a study out of the US National Institute of Diabetes and Digestive and Kidney Diseases: fourteen reality show contestants had been tracked for half a dozen years after appearing on the program The Biggest Loser. Through dieting and very intensive exercise, each had lost at least 50 pounds during their time on the television series—and a couple had shed more than 200—but the follow-up study found they’d regained about two-thirds of what they’d lost, on average. A handful ended up even heavier than when they first appeared on the television program.

This weight rebound came as no surprise. The tendency of dieters’ bodies to creep back toward prior weights has been among the most reliable and replicable results in the study of weight loss interventions. Research suggests that roughly 80%of people who shed a significant portion of their body fat will not maintain that degree of weight loss for 12 months; and, according to one meta-analysis of intervention studies, dieters regain, on average, more than half of what they lose within two years. Meanwhile, follow-up care that is meant to stave off this backsliding via behavioral or lifestyle interventions appears to be effective only at the margins: across several dozen randomized trials, the benefits of these programs—in terms of minimizing regain—were pretty small at two years, and undetectable thereafter. In short, we’ve known for quite some time that while it’s hard to lose weight, it’s even harder to keep it off.

The Biggest Loser study didn’t just recapitulate this disheartening rule of thumb, however. It appeared to offer something more—an explanation, of a sort, for why the weight rebound might be happening. When the researchers at the National Institute of Diabetes and Digestive Kidney Diseases, led by physiologist Kevin Hall, examined the contestants six years after the show ended, they noticed major changes to the rates at which their bodies were expending energy. The contestants’ resting metabolic rates had ended up much lower than expected, even taking stock of their smaller statures overall: most were burning at least 400 fewer calories than the researchers’ model had predicted. Some initial dip in metabolic rate is a known side effect of weight loss, but Hall and his colleagues didn’t realize that it would persist for so long, and to such a large extent.

“Dieters are at the mercy of their own bodies,” explained the write-up in the Times, in a lightbulb formulation that helped to make the story one of the newspaper’s top ten most read of the year (just a few slots south of ‘Donald Trump Is Elected President’). For many readers, or dieters, this would be a way to sop frustration with a dour fact of physiology—and find solace in the revelation that shedding weight provokes a natural reflex to regain.

The Biggest Loser study only gestured at the underlying scientific problem, though. Yes, dieters are at the mercy of their bodies, but their reflex to regain could be undergirded by a wide array of mechanisms, such as flagging satiety hormones, adaptations in the microbiome of the gut, and alterations to the makeup of their fat tissue. Changes to the metabolic rate may be thought of as one more factor on this list, as an outcome of a bunch of lower-level processes. In any case, the 2016 research, like other studies of this topic, has been nagged by a conundrum: how can you tell whether any single factor is in fact a cause of dieters regaining weight, as opposed to just a signal of their having gotten thinner in the first place?

That ambiguity shows up in the data from the reality show contestants. It’s true that almost all of the dieters’ resting metabolic rates had decreased across the follow-up, and that this change would have seemed to favor weight rebounds, all else being equal. But it also seems that their metabolic slowing was not the primary driving force of anyone’s weight regain. In fact, Hall and his colleagues found that contestants who showed up for testing six years later with the lowest metabolic rates were the same ones who actually had the most success in maintaining their weight loss. A lasting improvement to their exercise habits had allowed them to maintain a lower weight, and also apparently dampened their resting metabolic rates.

Ambiguities abound in the science of weight regain. One line of research, for example, looks at changes in circulating hormone levels in the aftermath of dieting. In a highly cited 2011 study published in the New England Journal of Medicine, Australian researchers put 50 overweight or obese people on a two-month diet of Optifast shakes and vegetables, yielding a total of about 500 calories per day. A year later, blood samples were collected from the patients for analysis of fasting and postprandial levels of ghrelin, leptin, peptide YY, amylin and other hormones.

The dieters had lost an average of 30 pounds during the initial intervention, and then gained back about a dozen pounds over the months that followed, when they were given advice on healthy nutrition and exercise habits, but were allowed to eat as they liked. Their endocrine markers showed a similar acute effect, followed by a partial rebound. Levels of the satiety-inducing hormone leptin, for example, initially dropped by almost two-thirds during weight loss when they were on the 500-calorie-per-day diet, but remained more than one-third reduced one year later, after all those months without dietary supervision. Similar patterns were seen for the other assays: across the board, it looked like dieting induced a rapid shift in hormone levels that would tend to favor increased appetite (and thus weight gain); and this effect would not return to baseline even after many months had passed.

Again, there was some murkiness regarding cause and effect. The study hinted that the drop in leptin levels, and other hormonal changes, might have been what spurred participants to gain back almost half of what they’d lost. But the hormonal changes could just as well have followed from the weight loss. Leptin levels in the plasma are known to drop during a very low-calorie diet, as well as when a person has been shedding fat. Contestants on The Biggest Loser, for example, saw their concentrations founder by almost 95 percent over the course of the weight-loss competition. That changes such as these might still be detectable, to some degree, 12 months down the road could just as well reflect the fact that the patients had maintained some degree of weight loss across that time, too.

That may be why follow-up attempts to predict the magnitude of a person’s weight regain from the depth to which his or her leptin levels drop have been largely unsuccessful. Kevin Hall wonders if the correlation between these two variables might even end up the reverse of what you might expect, as he’d found for resting energy expenditure. “If you’re the kind of person who can decrease your calorie intake and therefore lose a lot of weight,” he says, “then you’re going to experience the greatest decrease in leptin.” Furthermore, he speculates, if you’re the kind of person who is able to maintain that change in lifestyle, you’ll also be the kind of person whose leptin levels stay reduced.

A more comprehensive theory of weight regain, accounting for a broad array of mechanisms, may help address some of the confusion in this field. Researchers Marleen van Baak and Edwin Mariman of Maastricht University, for example, have proposed that the compensatory reflex begins with changes to the shape of fat cells. As these cells drain and shrink, their membranes pull away against the points of adhesion to the nearby extracellular matrix, creating mechanical stress. This in turn sets “a multitude of adaptations” in motion, they said in an interview, although the strength of these responses will differ across individuals.

According to their preliminary model, which is based on both in vitro studies of adipocytes and examinations of protein expression during and after weight loss, the mechanical tension that shedding weight creates at the fat-cell membranes inhibits further fat release and primes those cells to be filled again. At the same time, they theorize caloric restriction may deprive adipose tissue of the energy it would need to relieve this stress through remodeling of the extracellular matrix. The stress response could also lead to changes in the adipocytes’ secretion of leptin and other signaling proteins, and persistent inflammation in the aftermath of someone losing weight.

The Maastricht group has been looking to support this theory with data from the “YoYo study”: a randomized controlled trial of around 60 participants who were placed on either an intense crash diet (of 500 calories per day over 5 weeks), or a slower one (of 1,250 calories per day over 12 weeks). This was followed by a brief weight-stabilization period (in which they received about as many calories as they would need to keep a constant weight) and then further check-ins for the next nine months. The team took biopsies of adipose tissue at the end of each study phase, measured changes to its gene activity, and checked to see which, if any, might be correlated with weight regain. In a subgroup analysis of the crash diet participants, 15 genes related to the extracellular matrix were identified, and 8 more associated with stress response.

Others are looking for answers in the genome. “At this point in time, people are still adding different pieces to the puzzle,” says Jeanne McCaffery of the University of Connecticut. Her own puzzle piece relates to the question of inherited genetic risk for weight regain: “We were excited about the hypothesis that if you were genetically disposed to have a higher body weight, you’d put on weight again more quickly,” she adds. But a genome-wide association study to determine whether genes that have been linked to the development of obesity might also be predictive of weight regain failed to turn up any positive results. That could be on account of its insufficient sample size, McCaffery explains. The study had about 3,000 people in the weight-loss condition, whereas similar studies of the genetics of obesity have been far larger in scope.

The one point on which nearly all researchers agree is that the physiology of weight regain, like the physiology of obesity itself, is almost certain to reflect a very complicated mix of factors ranging from genetics to behavior and the environment. That means we’re unlikely to find any magic-bullet method for keeping pounds from coming back. Indeed, some degree of rebound may be more or less inevitable for the majority of dieters.

But even that news may not be as bad as it seems. Just last year, a team of researchers at the University of Alabama at Birmingham, led by David Allison, put out a rodent study of a provocative idea: what if there were lasting benefits to losing weight—even when that weight is almost certain to be regained? The researchers randomized 552 obese, Black-6 mice into four groups: one set of animals ate a high-fat diet at will and remained obese; another two sets received either moderate or more extreme caloric restriction, and stabilized at a ‘normal’ or intermediate weight; and a fourth was put through several yo-yo cycles of restricted and ad libitum feed, losing weight and then gaining it right back.

At the end of the study, the mice that remained obese throughout the experiment had markedly increased mortality: they lived, on average, for just 21 months, as compared to the 26-month average lifespan of the mice that had been put on the most extreme diets and kept at a normal weight. More surprising was the fact that the yo-yo mice also gained longevity, by virtue of their weight cycling: they lived an average of 23 months, about the same as the mice that were kept under chronic, moderate calorie restriction.

In other words—at least for mice—it may be that weight regain doesn’t cancel out all the benefits of dieting. Those who feel they’re going around in circles may take some solace in this notion: even if your fat cells tug and twist your weight loss back to zero, that doesn’t mean that you’ve been pulled back to where you started.

This article is reproduced with permission and was first published on November 7, 2019.