Is our ability to choose what we eat truly free? This intriguing question is central to understanding why many individuals struggle to adhere to a diet.
Neuroscientist Harvey J. Grill from the University of Pennsylvania explored this by studying rats. He removed all parts of their brains except for the brainstem, which governs basic functions like heartbeat and respiration. However, these rats lacked the ability to see, smell, or remember.
Would these rats still be aware of when they had eaten enough?
To explore this, Dr. Grill administered liquid food directly into their mouths.
“Once they reached their limit, they let the food spill out,” he explained.
These experiments, initiated years ago, laid the groundwork for ongoing research that has consistently surprised scientists, underscoring that the sensation of fullness in animals is independent of conscious thought. This insight is increasingly significant as researchers unravel how emerging weight-loss medications, such as GLP-1s (including Ozempic), influence the brain’s mechanisms for controlling eating.
The findings provide insight not on why some individuals become obese while others don’t, but rather on what triggers our eating and when we stop.
Although most research has focused on rodents, Dr. Jeffrey Friedman, an obesity expert at Rockefeller University in New York, emphasizes that humans share similar evolutionary traits which shaped complex neural pathways that dictate our eating behavior.
Researchers have discovered that the brain continuously receives signals indicating the caloric density of food. The body has specific caloric needs, and these signals help ensure those needs are met.
This process starts even before an animal takes its first bite. Just seeing food activates neurons that predict how many calories may be in it. These neurons respond much more vigorously to high-calorie foods like peanut butter compared to low-calorie options such as mouse chow.
The next stage occurs once the animal tastes the food: Neurons reassess the caloric density based on signals transmitted from the mouth to the brainstem.
Finally, as the food reaches the gut, additional signals are sent to the brain, allowing neurons to evaluate the caloric information once more.
Interestingly, it is the caloric content that the gut assesses, as Zachary Knight, a neuroscientist at the University of California San Francisco, discovered.
He demonstrated this by infusing three different types of food into the stomachs of mice: fatty food, carbohydrates, and protein, all with the same caloric content.
In every instance, the messages sent to the brain were identical: neurons signaled the energy content in calories, regardless of the calorie source.
When the brain determines that sufficient calories have been consumed, neurons signal the cessation of eating.
Dr. Knight expressed surprise at these findings, as he had previously assumed the stop signal involved communication between the gut and brain, where a sensation of fullness would lead to the decision to stop eating.
Following this logic, many dieters attempt to drink water before meals or eat low-calorie foods like celery.
However, these strategies often fail because they don’t consider how the brain regulates eating. Dr. Knight found that mice do not send signals of fullness to the brain when only water is consumed.
It’s true that individuals can choose to eat even when they don’t feel hungry, or refrain from eating while trying to lose weight. Dr. Grill noted that in a fully functioning brain—not just the brainstem—other brain regions also play a significant role in this process.
However, Dr. Friedman pointed out that, ultimately, the brain’s mechanisms often override conscious choices about the need to eat. He likened it to holding one’s breath—possible for a short time but ultimately limited. Similarly, one can suppress a cough, but only up to a certain point.
Scott Sternson, a neuroscientist at the University of California in San Diego, concurred.
“Much of appetite control operates automatically,” said Dr. Sternson, who co-founded Penguin Bio, a company working on obesity treatments. While people can choose to eat or not at a given time, he noted that managing this kind of control demands significant mental energy.
“Eventually, attention shifts to other priorities, and the automatic process tends to prevail,” he explained.
As researchers examined the brain’s eating controls, they were repeatedly astonished.
They discovered, for example, how quickly the brain responds to merely the sight of food.
In studies involving mice, neuroscientists identified thousands of neurons in the hypothalamus that activate in response to hunger. However, they were uncertain how these neurons were regulated. Previous research had shown that fasting activated these hunger neurons, while they were less active in well-fed animals.
The prevailing theory suggested that these neurons reacted to the body’s fat reserves. When fat stores are low—such as during fasting—levels of leptin, a hormone produced by fat, also drop, activating hunger neurons. As an animal eats, fat stores rebuild, leptin levels rise, and it was assumed the neurons would quiet down.
This system was believed to have a sluggish response to the body’s energy storage state.
However, three independent research teams led by Dr. Knight, Dr. Sternson, and Mark Andermann from Beth Israel Deaconess Medical Center began investigating the immediate activity of hunger neurons.
They commenced with hungry mice whose hunger neurons were firing rapidly, indicating the animals required food.
The unexpected event occurred when the researchers presented food to the animals.
“Before even tasting the food, the activity in those neurons ceased,” explained Dr. Knight. “The neurons were making a prediction. The mouse sees food and anticipates how many calories it might consume.”
The higher the calorie content of the food, the more neurons become inactive.
“All three labs were taken aback,” remarked Dr. Bradford B. Lowell, who collaborated with Dr. Andermann at Beth Israel Deaconess. “It was quite surprising.”
Dr. Lowell then inquired about the effects of intentionally disabling the hunger neurons while the mice were still hungry. Researchers can achieve this through genetic changes that allow them to activate or deactivate neurons with either a drug or blue light.
These modified mice would refrain from eating for hours, even with food readily available.
In a different experiment, Dr. Lowell and Dr. Sternson activated the neurons in mice that had just enjoyed a large meal, akin to a Thanksgiving feast. The mice were relaxed and feeling full.
However, according to Dr. Andermann, who repeated the experiment, when they activated the hunger neurons, “The mouse gets up and consumes an additional 10 to 15 percent of its body weight.” He added, “The neurons are signaling, ‘Just concentrate on eating.’”
Researchers remain astonished by their findings—various mechanisms in the brain that meticulously manage eating behavior. They also see potential for developing new medications to regulate appetite.
One significant discovery came from Amber Alhadeff, a neuroscientist at the Monell Chemical Senses Center and the University of Pennsylvania. She recently identified two distinct groups of neurons in the brainstem that respond to GLP-1 drugs used for obesity.
One group of neurons indicated that the animals had consumed enough food, while the other group triggered a rodent-like nausea response. The existing obesity medications affect both groups of neurons, according to her findings, which could explain the side effects many experience. She suggests that it may be feasible to create drugs targeting only the satiety neurons, avoiding the nausea-related ones.
Alexander Nectow from Columbia University has made another surprising discovery. He found a cluster of neurons in the brainstem that govern the desired size of a meal, monitoring each bite taken. “We are still trying to understand how they accomplish this,” he stated.
“I have been researching this brainstem area for over 15 years,” Dr. Nectow noted, “but employing our advanced tools helped us uncover this neuron group we had never examined before.”
He is now exploring whether these neurons could serve as targets for a new category of weight-loss medications that could surpass the effectiveness of GLP-1s.
“That would be truly remarkable,” Dr. Nectow expressed.
