For much of his life, 32-year-old Michael Smith had a war going on in his head. After a big meal, he knew he should be full. But an inexplicable hunger would drive him to pick up the fork again. Cravings for fried chicken or gummy bears overwhelmed him, fueling late-night DoorDash orders that — despite their bounty of fat and sugar — never satisfied him.
He recalls waking up on the couch, half-eaten takeout in his lap, feeling sluggish and out of control. "It was like I was food drunk," recalls Smith, who lives in Boston, Massachusetts. "I had a moment I looked at myself in the mirror. I was around 380 pounds, and I said, 'OK, something has got to give.'"
Smith is among the 42% of US adults living with obesity, a misunderstood and stubbornly hard-to-manage condition that doctors have only recently begun to call a disease. Its root causes have been debated for decades, with studies suggesting everything from genes to lifestyle to a shifting food supply loaded with carbohydrates and ultraprocessed foods. Solutions have long targeted self-discipline and a simple "eat less, move more" strategy with remarkably grim results. Those who successfully slim down tend to gain back 50% of that weight within 2 years and 80% within 5 years. Meanwhile, the obesity epidemic marches on.
But a new frontier of brain-based therapies — from glucagon-like peptide-1 (GLP-1) agonist drugs thought to act on reward and appetite centers to deep brain stimulation aimed at resetting neural circuits — has kindled hope among patients like Smith and the doctors who treat them. The treatments and theories behind them are not without controversy. They're expensive, have side effects, and, critics contend, pull focus from diet and exercise. But most agree that in the battle against obesity, one crucial organ has been overlooked. "Obesity, in almost all circumstances, is most likely a disorder of the brain," said Casey Halpern, MD, an associate professor of neurosurgery at the University of Pennsylvania, Philadelphia. "What these individuals need is not simply more willpower, but the therapeutic equivalent of an electrician that can make right these connections inside their brain."
Throughout the day, the machine that is our brain is constantly humming in the background, taking in subtle signals from our gut, hormones, and environment to determine when we're hungry, how food makes us feel, and whether we are taking in enough energy, or expending too much, to survive. "We like to think that we have control over what we eat, but the brain is also integrating all of these factors that we don't fully understand in ways that shape our decisions," said Kevin Hall, PhD, an obesity researcher with the National Institute of Diabetes and Digestive and Kidney Diseases. "I liken it to holding your breath. I can do that for a period of time, and I have some conscious control. But eventually, physiology wins out."
Mounting evidence suggests that in people with obesity, something in the machine is broken. One seminal 2001 study in The Lancet suggested that, like people addicted to cocaine or alcohol, they lack receptors to the feel-good brain chemical dopamine and overeat in pursuit of the pleasure they lack. A recent study, not yet published, from Hall's lab drew a slightly different conclusion, suggesting that people with obesity actually have too much dopamine, filling up those receptors so the pleasure spike from eating doesn't feel like much. "It's kind of like trying to shout in a noisy room. You're going to have to shout louder to have the same effect," said Hall. Gut-brain pathways that tell us we're full may also be impaired.
In another study, Yale researchers tube-fed 500 calories of sugar or fat directly into the stomachs of 28 people with normal weight and 30 people with obesity and observed their brain activity using functional magnetic resonance imaging. In people with normal weight, about 30 regions of the brain quieted after the meal, including parts of the striatum (associated with cravings). In those with obesity, the brain barely responded at all. "In my clinic, patients will often say 'I just finished my dinner, but it doesn't feel like it,'" said senior author Mireille Serlie, MD, PhD, an obesity researcher at the Yale School of Medicine, New Haven, Connecticut. "It may be that this nutrient-sensing interaction between the gut and the brain is less pronounced or comes too late for them after the meal."
Halpern recently identified a brain circuit linking a memory center (hippocampus) to an appetite control region (hypothalamus). In people with obesity and binge eating disorder, the circuit appears jammed. This may cause them to, in a sense, forget they just ate. "Some of their eating episodes are almost dissociative — they're not realizing how much they are eating and can't keep track of it," he said. Another brain system works to maintain longer-term homeostasis — or weight stability. Like a set thermostat, it kicks on to trigger hunger and fatigue when it senses we're low on fat. The hormone leptin, found in fat cells, sends signals to the hypothalamus to let it know how much energy we have on board.
"If leptin levels go up, it signals the brain that you have too much fat and you should eat less to return to the starting point," said Rockefeller University geneticist Jeffrey Friedman, MD, PhD, who discovered the hormone in 1994. "If you have too little fat and leptin is low, that will stimulate appetite to return you to the starting point." In people with obesity, he said, the thermostat — or set point the body seeks to maintain — is too high. All this raises a crucial question: How do these circuits and pathways malfunction in the first place?
Studies show that genetics underlie as much as 75% of people's differences in body mass index, with certain gene combinations raising the risk for obesity in particular environments. While hundreds of genes are believed to have a small effect, about a dozen single genes are thought to have a large effect. (Notably, most influence brain function.) For instance, about 6% of people with severe obesity since childhood have mutations in a gene called melanocortin 4 receptor, which influences leptin signaling. Still, genetics alone cannot account for the explosion in obesity in the United States over the last 50 years, says epidemiologist Deirdre Tobias, ScD, an assistant professor of medicine at Harvard Medical School, Boston, Massachusetts. At the population level, "our genes don't change that much in less than a generation," she said. But our food supply does.
Ultraprocessed foods — those containing hydrogenated oils, high-fructose corn syrup, flavoring agents, emulsifiers, and other manufactured ingredients — now make up about 60% of the food supply. "The evidence is fairly consistent indicating that there's something about these foods that is possibly causing obesity," said Tobias. In one telling 2019 study, Hall and his colleagues brought 20 men and women into a study center to live for a month and tightly controlled their food intake and activity. One group was provided with meals with 80% of calories from ultraprocessed food. The other was given meals with no processed food. The three daily meals provided had the same calories, sugars, fats, fiber, and carbohydrates, and people were told to eat as much as they wanted. Those on the ultraprocessed diet ate about 500 calories more per day, ate faster, and gained weight. Those on the unprocessed diet lost weight. "This is a stark example of how, when you can change the food environment, you cause really remarkable changes in food intake without people even being aware that they are overeating," said Hall.
Just what it is about these relatively novel foods that may trigger overeating is unclear. It could be the crunch, the lack of water content, the engineered balance of sugar/salt/fat, their easy-to-devour texture, or something else. Some research suggests that the foods may interfere with gut-brain signaling that tells the brain you're full. "Evidence is amassing that the nutritional content of processed foods is not accurately conveyed to the brain," wrote Dana Small, PhD, a neuroscientist at Yale, in a recent perspective paper in Science. Even more concerning: Some animal studies suggest processed foods reprogram the brain to dislikehealthy foods.
And once these brain changes are made, they are hard to reverse. "The problem is our brain is not wired for this," said Halpern. "We are not evolved to eat the food we are eating, so, our brain adapts, but it adapts in a negative way that puts us at risk." That's why changing the food environment via public policy must be part of the solution in combating obesity, Tobias said.
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