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Solving Obesity: New Drugs Can’t Change How Little We Know

This is the first in a three-part series on the obesity crisis. Part two examines if new weight loss drugs will finally end the obesity crisis. Part three shows how doctors and patients can make treatment even better.

July 5, 2023 – Everyone’s talking about weight loss drugs. 

The craze began when word leaked about Hollywood types using Ozempic and Wegovy to drop weight. Like a Southern California wildfire, news spread: These injectable drugs could help people lose 10%, 15%, or even 20% of their body weight.

Now we’ve blown by the tipping point. More weight loss meds are on the way, some in pill form. In the latest breakthrough, people in a phase II clinical study who took the drug retatrutide lost 24% of their body weight. That’s almost on par with bariatric surgery. 

Doctors (and drug companies) are thrilled, and they should be: These are the first drug treatments for obesity that work. Or, at least, the first to work well. 

Yet, while these drugs may be a major win for obesity treatment, all the celebratory noise can’t erase a sobering truth: There’s still a lot we don’t know about obesity, including what’s behind an unprecedented spike in obesity rates over the past 30-plus years and, crucially, how to prevent obesity in the first place. 

Heck, researchers aren’t even sure how this class of drugs – GLP-1 agonists – works for weight loss. Diabetes was the original target, and weight loss effects were a surprise. 

“The most effective drug we have for obesity was developed by accident,” said Dariush Mozaffarian, MD, a cardiologist and nutrition professor at Boston’s Tufts School of Medicine. “That right there should be a clear sign of how little we understand about obesity.”

So Much Research, So Few Answers 

More than 40% of American adults live with obesity. Sixty years ago, that number was 13%.

In some ways, that’s the medical failure of our time. No matter what we’ve done or how much science has uncovered, we’ve just kept gaining weight – even as rising childhood obesity rates have filled the pipeline.

Around the turn of the century – after the obesity rate soared in the ’90s – scientists responded with an explosion of research. As study after study linked excessive fat to the deadliest diseases – cardiovascular disease, strokes, diabetes, cancer – the obesity fight emerged as a clear public health priority. In the last decade alone, the U.S. has invested almost $11 billion in this research. Yet there’s no evidence to suggest we can halt or reverse the trend. The biggest tell: Even obesity researchers acknowledge their failures. 

Time will reveal the drugs’ impact, but it may be limited, given how widespread obesity has become. 

The problem: The list of potential causes of obesity is so long, it’s hard to pick one, much less decide how to fix it. Diet and intervention studies can tell us only so much. Few are definitive, and most leave ample room for debate. 

“The underlying cause [of obesity], and therefore the issues that would guide prevention, are very difficult,” said Randy Seeley, PhD, director of the National Institutes of Health-funded Michigan Nutrition Obesity Research Center. “We’ve run lots of different trials to do obesity prevention, and almost all have been abject failures.” 

We Americans Just Eat Too Much, Right?

Overeating may be the most widely accepted explanation for rising obesity numbers. It feels intuitive: We eat too much and move too little. Which leads to the “we Americans just love our large portions and sugary foods more than our health” take.

But what if there were data to suggest that, in fact, our food intake has not changed in 20 years – even as the obesity rate has soared? 

There is. Picture a chart with three lines. One line represents total food intake, and another our total food supply. A third line – the obesity rate – rises sharply, ultimately surpassing the other two, which stay flat. 

“By two independent measures, calorie intake has been flat in the U.S. for 20 years while obesity has skyrocketed,” says Mozaffarian. “That single point should call into question everything we think we know.” 

He revealed this plot twist in a perspective paper he wrote last year. The data is from the National Health and Nutrition Examination Survey on what we eat, and the Food and Agriculture Organization, which tracks the food supply. 

When you consider our growing body sizes, “the data suggest that Americans have been eating relatively less,” the paper notes. It says there’s little evidence to suggest physical activity has changed either, undermining the idea that declining exercise could be a driver. 

As often happens in this field, the argument leaves plenty of room for skepticism. Much of the data in question is based on people reporting their own behavior, and that can be unreliable – people may under-report how much they eat and over-report how much they move. Plus, while overall population data may show steady trends, this may hide differences in important subgroups, said Walter Willett, MD, DrPH, a professor of epidemiology and nutrition at the Harvard T.H. Chan School of Public Health. 

That is, some groups (such as those in low-income areas) may be eating more and moving less, while others (in more privileged parts) are eating less and moving more – so overall, the line appears flat. What’s more: “If you look back farther, food consumption has gone up since the 1970s,” Willett says. That’s right around the time the average body weight began to rise. 

Mozaffarian acknowledged these limitations in his paper but said “discarding all these data because they do not fit a conventional theory of obesity would be imprudent; and other hypotheses must also be considered.”

An alternate explanation: The quality of our food intake – like all those sugars and processed carbs – may have changed our bodies’ response to food.

Take the microbiome.  Rodent studies show that changes in the microbes that live in your gut may impact metabolism and body weight. (Some research suggests that fecal transplants may improve the metabolic health of subjects with obesity, but much more research is needed before this can be used to treat people.) 

Another possibility is the impact of diet on our epigenetics, or the way our genes work. “Epigenetics is something on top of the genetic environment that allows some genes to turn on and off,” said Margarita Teran-Garcia, MD, PhD, an obesity researcher at the University of Illinois Urbana-Champaign, who studies interactions between biology and environment. Nutrients, like fat or carbs, may do this to genes that burn or store energy, playing a role in fat storage. 

These are emerging areas that scientists are still working to understand. 

“I would say we’re maybe 5% of the way there in what we know. And there’s still 95% that’s understudied,” Mozaffarian says. 

What Do We Know From 40 Years of Research?

Trying to summarize obesity research is overwhelming. So many studies, so many caveats, contradictions, and dead ends. 

Arguably the biggest landmark was the discovery of leptin, a fat hormone that regulates body weight, in 1994. 

“It was the discovery of leptin that changed things … that said it’s not just willpower; there’s biology at work,” said James Hill, PhD, director of the Nutrition Obesity Research Center at the University of Alabama at Birmingham. “A lot of scientists started saying, ‘Wow, this problem of obesity is pretty interesting. I might want to look at it.’” 

The studies began rolling in. In 1990, scientists published 1,900 papers on obesity, according to a search of PubMed, a website that catalogs scientific research. By 2000, that number had more than doubled, and it has risen exponentially ever since, topping 33,000 papers annually for the last 3 years. All told, that’s nearly half a million studies.

Neuroscientists study rodents to see how the brain regulates food intake. Geneticists identify human genes linked to obesity. (Hundreds have been found so far.) Epidemiologists survey large populations, looking for patterns linked to weight gain, weight maintenance, or weight loss. 

Nutrition researchers do diet studies, dividing people they study into groups assigned to different diets. These are notoriously hard to design. Most rely on people to follow the nutrition advice, and few last more than a year. 

“‘Oh, there’s a professor who has a question. I promise to change my diet and perfectly adhere to it for the next few decades!’ No one is going to sign up for that study,” said Christopher Gardner, PhD, director of nutrition studies at Stanford Prevention Research Center. 

Most diet studies show no one diet is better for weight loss than another. Any diet can work if you reduce calories. 

Still, results vary a lot. In one large diet study from Gardner in 2018, people following a low-carb or low-fat diet found a wide variety of outcomes: Some lost as much as 50 pounds, while others gained up to 20.

“A 70-pound range,” Gardner said. “How can you explain that when they got the same advice?” (In fact, that was the very question Gardner had set out to answer, but he found no link between people’s success and their genetics or insulin response.) 

The thing is, we do know how to lose weight – the problem is keeping it off. High-quality data on long-term weight loss is sparse, but what little we have suggests most people regain lost pounds within 5 years. 

“We have not, as a health professional community, been very successful with helping people lose fat and maintain that loss,” Gardner said.

For Hill – who in the 1990s co-founded the National Weight Control Registry, a study tracking 10,000 people who’ve lost weight and kept it off – that’s because people are “swimming upstream.” 

“Really good swimmers can do it, but most get swept down,” Hill said. “We can either teach people to be better swimmers, or we can reduce the current, which is the environment.”

Both of those options are easier said than done.

That Pesky Environment

The overall trend of obesity research has been a shift to understanding obesity as a disease. 

Like many diseases, obesity is likely caused by a combination of genetics and our environment, said Samuel Klein, MD, a professor of medicine and nutritional science at Washington University School of Medicine in St. Louis.

“Computers, cars, and cellphones keep us sitting in one place,” he said. “We have food that doesn’t perish. We can keep it in a can or frozen for months or years. We’re never without the availability of food.” 

Many researchers agree, but exactly what parts of that environment are to blame, and how they interact with our bodies, is hotly debated.

Some theories:

  • The prevailing view focuses on the brain. Brain circuits that control food intake are responding to a changing food environment in ways that are still being revealed, resulting in overeating and obesity. (One new study found that obesity may permanently impair the brain’s response to eating fats and sugars, making people less able to recognize when they’re full.)
  • A competing hypothesis – the carbohydrate-insulin model – suggests that highly processed carbohydrates trigger hormonal responses that lead to excess fat storage. 
  • Yet another view suggests that chemicals called obesogens (found in products like can linings, plastic bottles, clothing, and pesticides) lead to weight gain by altering hormones and metabolism in ways that promote fat. 

Still other societal changes may be at play. Weight gain is a side effect of many antidepressants and other treatments for mood disorders, said Louis Aronne, MD, director of the obesity research and treatment program at Weill Cornell Medicine, at Cornell University in New York City. “We estimated in a paper that about 15% of the obesity epidemic could be related.” 

Indoor temperature controls mean we burn fewer calories warming up or cooling down. Changing sleep habits can impact weight. Far fewer people smoke now, a huge health win no doubt. But when people stop smoking, they tend to gain weight. 

And the list goes on. All of the above? Perhaps. But good luck getting a consensus.

“Most obesity researchers will tell you that we really don’t know why obesity occurs,” Hill said. “We know a lot, but I can’t sit here and say, ‘Here is why we have so much obesity.’”

Can a new class of weight loss drugs end the obesity epidemic? Read part two here.

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