Ozempic and Wegovy show us that obesity is not an option – 02/13/2023 – Equilíbrio

In a girl’s house in Hertfordshire, England, you need a key code to enter the kitchen, where all the cupboards are padlocked and the rubbish bin is locked. Without these measures, the child – whose name cannot be disclosed because he is currently in foster care– would not be able to stop eating, even raw meat or pasta leftovers thrown in the trash.

“She is constantly on the lookout for any possibility of access to food,” like a missile in search of calories, her adoptive father told me. Her brain doesn’t register that she ate. So she lives with a constant, raging hunger, a pervasive obsession about her next meal or snack, something that distracts her from her other interests – dolls, horseback riding and drawing.

At 12, the girl is thin, she looks like a little bird. If her adoptive parents hadn’t supervised every bit, she would be a lot bigger, like many people who have the same disease, Prader-Willi syndrome. Prader-Willi patients can eat so much that, in extreme cases, their stomachs burst, causing their death.

The disease has a rare and devastating genetic cause of obesity. But it also exists at the extreme end of a spectrum of eating behavior common to all of us, as Tony Goldstone, an endocrinology researcher at Imperial College London and a physician who works with Prader-Willi patients, told me recently. “People think they only eat because they want to eat, or because they’ve decided to eat rationally,” Goldstone said. “But a lot of it doesn’t happen at the conscious level.”

We tend to believe that body size is something we can totally control, that we are thin or fat because of deliberate choices we make. After talking with hundreds of obesity patients over the years, and with doctors and researchers who study the disease, I can assure you: reality is a lot less like free will.

The emergence of new and effective anti-obesity drugs provides a clear illustration of this underappreciated fact of physiology. The drug-provoked debates also show how little we like obesity.

Biological systems, influenced by our environments and our genes, control the flow of energy through us: energy enters the body in the form of food and is consumed or stored in our bodies, primarily as fat. These systems, arising from interactions between the brain and the body, are largely involuntary. They work involuntarily, like our reproductive drive or the mechanisms that stabilize our body temperature.

The Hertfordshire child with Prader-Willi “has an abnormality in the energy balance thermostat in her brain and is unresponsive,” Goldstone said. But she experiences just a variation of the kinds of hunger and fullness cues we all live with.

It is relatively easy to understand that the environment influences our eating behavior and how much weight we gain.

“Living near a farmers’ market or in a food desert will have a much greater influence on whether a person makes healthy food choices than how much self-discipline they have,” Dan Brierley, a neuroscientist at University College London who studies obesity, told me. Many of us live in places full of cheap, ultra-processed calories, which may help explain rising obesity rates.

But not everyone has obesity today. That’s because the way we react to the environment is also subject to internal controls – invisible nudges that guide us through each meal. Researchers have observed this for over a hundred years and have only recently begun to unravel how these systems work. A new class of diabetes and obesity drugs — such as semaglutide (sold under the brand names Ozempic and Wegovy) and tirzepatide (Mounjaro) — evolved from that research.

The cascade of discoveries that led to these injectable drugs, considered the most effective ever approved for obesity, can be traced back to the 1840s, when physicians began sharing case studies of patients who, for reasons that seemed beyond their conscious control, they ate too much to the point of severe obesity.

On closer examination, many had brain tumors. The tumors interfered with their physiology in mysterious ways that changed what and how much they ate.

Animal studies that followed suggested a new understanding of what was going on: body weight and eating behavior were regulated, not just the product of conscious control, and the brain somehow orchestrated the process.

Genes also seemed to play a role. Scientists had long observed that obesity ran in families, but it was not clear how much heredity or environment accounted for this. A famous 1990 study of identical twins born in Sweden showed that pairs who were separated at birth and adopted were more similar in weight to each other than to their adoptive families.

In the mid-1990s, scientists looked into this complex machinery to see at the molecular level how brains and genes shape appetite and weight. Initial studies with mice revealed that the rodents produce a factor that sends a signal to the brain about the amount of body fat stored in them. Some mice with obesity lacked this factor and could not stop eating. Researchers at Rockefeller University, in New York, identified the factor in 1994: it was a hormone, which they named leptin, encoded by a gene known as LEP.

Later, researchers at the University of Cambridge discovered the role of leptin in humans after encountering patients with extreme forms of childhood obesity caused by LEP mutations.

As in mice, leptin is produced by body fat and transported into the bloodstream, from where it circulates to the brain. There she sends a message about how much energy is stored in the body in the form of fat. When leptin levels drop, or people have genetic abnormalities that don’t allow them to make leptin or register the leptin signal, the brain reads that there is not enough fat in the body, and people feel hungry and eat more.

Although leptin regulates energy balance over time horizons such as weeks, there are many other signals that guide our nutritional choices from meal to meal (just as there are now over a thousand known genetic variants implicated in obesity).

One well-known player is the hormone glucagon-like peptide-1, or GLP-1, which Wegovy and Ozempic mimic. Produced mainly by the intestine, it tells the brain when we’ve had enough to eat.

The ability to sense that fullness — and hunger — varies, the result of genetic differences in the brain circuits that control appetite. This manifests itself in a variety of experiences, from people with Prader-Willi to that friend who forgets to eat and is effortlessly thin all her life (and therefore perhaps cannot understand why anyone struggles with weight).

The new drugs are the first to manipulate the hormonal regulatory systems that govern energy balance. The drugs mimic the action of our native GLP-1, but with longer-lasting effects, amplifying the fullness signal within the body. People who struggle to feel full suddenly don’t, effectively giving “someone the ‘willpower’ of those lucky enough to win the genetic lottery,” Brierley said.

Many people who have taken obesity medication have described to me how their experience of hunger had fundamentally changed. Patricia McEwan, who injected Ozempic for nine months, said she intended to stay on the drug for life because it “turned off the constant, intrusive thoughts about food” that had consumed so much of her mental space since childhood.

Before Ozempic, McEwan thought that overeating was driven by his emotions and lack of willpower. After Ozempic, she understood that her reaction to food was a product of her physiology.

There are open questions about how GLP-1-based drugs will work in the long term in individual patients and what impact, if any, they will have on the rising global rate of obesity. The data we have suggests that people’s weight loss can plateau after a while, and side effects are common, as is weight regain when patients stop taking the drugs.

There are many reports of health insurance hurdles or supply shortages interrupting or blocking people’s access to obesity drugs in the United States, and it’s not clear how low-income people will gain access to them. Meanwhile, the energy-balance model of appetite regulation is being complicated by evidence that we have other kinds of appetites for nutrients — for protein, for example — and there is very little understanding of how drugs will affect them.

At the very least, though, the way drugs work can teach us that bigger people don’t necessarily choose to be, any more than smaller people did — and aren’t morally superior.

This “is not a free pass, either for individuals who have the ability to choose better, nor does it take the weight off the food industries,” said nutritional biologist Stephen Simpson of the University of Sydney (Australia), but it is “evidence that obesity is not a personal lifestyle choice”.

Learning about this science has helped me see my own weight changes in a new light. When I became pregnant with my second child, I quickly developed a voracious appetite. I was hungry like never before, obsessed about my next snack or meal in ways I’m not used to, and ate amounts I would have found unimaginable (even unbearable) a few weeks earlier. I also gained weight quickly.

All of a sudden, in my second trimester, the increased appetite and weight gain subsided. But the preoccupation with food I had just experienced was reminiscent of my early years when I struggled with obesity. Now I could see that the changes weren’t the result of a sudden lack of willpower. My brain was telling my body to get more energy to support the growing fetus.

How women’s brains and bodies deal with this during pregnancy and breastfeeding is still a mystery, a phenomenon that has also been observed in lactating mice that tend to eat three times their usual calories. Some people with obesity are plagued by the kind of hunger I felt all the time during pregnancy. It is also not an option for them.

Translated by Luiz Roberto M. Gonçalves