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. “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 U.S. 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 ultra-processed 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 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, associate professor of neurosurgery at the University of Pennsylvania. “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.”
A Break in the Machine
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.
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 Dr. 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 Dr. 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 lean people and 30 people with obesity. Then they observed brain activity using functional magnetic resonance imaging (fMRI).
In lean people, 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. “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.”
Dr. 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?