We’ve never understood how hunger works – that might be about to change

Scientists have spent decades trying to unravel the intricate mysteries of the human appetite. Are they on the verge of finally determining how this basic drive functions?

You haven’t seen hungry until you’ve seen Brad Lowell’s mice. A few years ago, Lowell — a Harvard University neuro­scientist — and a postdoc, Mike Krashes, figured out how to turn up the volume on the drive for food as high as it can go.

They did it by stimulating a bundle of neurons in the hypothalamus, an area of the brain thought to play a key role in regulating our basic needs. 

A video captures what happened next. Initially, the scene is calm as a camera pans slowly along a series of plastic cages, each occupied by a docile, well-fed mouse, reclining on a bed of wood chips. None of the eight mice shown are interested in the food pellets arrayed above them on the other side of a triangular metal grate that drops down from the ceiling. Which is not surprising, since each mouse has just consumed the rodent equivalent of a Thanksgiving dinner.

But as the seconds displayed on a timer at the bottom of the screen tick away, half the mice begin to stir — the first evidence that a chemical agent designed to turn on specific neurons associated with appetite is reaching its targets. 

Soon, the mice seem possessed. Some stand on their hind legs, thrusting their noses through the grates above them at the inaccessible pellets. Others climb the walls, hang from the bars of the grate, or dig frantically through the wood chips.

“It looks like they’re losing their minds,” Lowell says.

Lowell, who is one of the world’s leading experts on the circuits in the brain that control hunger, satiety, and weight regulation, sometimes references this video to make a point:

When you’re starving, hunger is like a demon. It awakens in the most ancient and primitive parts of the brain and then commandeers other neural machinery to do its bidding until it gets what it wants. 

What might begin as a small sensation quickly spirals. Intrusive thoughts pulled from our memory centers burst into our consciousness. Images of meatball sandwiches. The smell of bread. The imagined taste of a cork-like food pellet. The motivational and emotional areas of our brain infuse the need to eat with a nonverbal imperative that feels so powerful it eclipses all else.

Our prefrontal cortex kicks into gear, considering how we might obtain food. (If we are in a dangerous situation like a war zone, we weigh how much danger we are willing to risk to get it.) Then we mobilize our sensory and motor areas. We steal a chicken, attempt to spear a fish in a pond, raid the work refrigerator, or hurl our body against a metal grate, hoping to get a taste of a food pellet.

So by exciting the hunger neurons in those mice, Lowell catalyzed a storm of neural activity that spread to the cerebral cortex and other higher-order processing centers, leading directly to a chain of complex goal-directed behaviours (ineffective though they turned out to be). 

It also drove home for Lowell just how much we still have to learn. 

“Sure, we managed to have the brain say ‘Go eat,’” Lowell says. “But that’s not really an explanation. How does that actually work?”

To answer that question, Lowell has teamed up with Mark Andermann, a neuroscientist who studies how motivation shapes perception (and who also happens to occupy the office next to his at Boston’s Beth Israel Deaconess Medical Center).

Together they are following known parts of the neural hunger circuits into uncharted parts of the brain, in some cases activating one neuron at a time to methodically trace new connections through areas so primitive that we share them with lizards. 

Their work could have important implications for public health. More than 1.9 billion adults worldwide are overweight and more than 650 million are obese, a condition correlated with a wide range of chronic health conditions, including diabetes, fatty liver disease, heart disease, and some types of cancer. Understanding the circuits involved could shed new light on the factors that have caused those numbers to skyrocket in recent years.

And it could also help solve the mystery behind a new class of weight-loss drugs known as GLP-1 agonists. Many in the field of public health are billing these drugs, which include Wegovy and Ozempic, as transformative, providing the first effective method of combating obesity, and allowing some individuals to lose more than 15% of their body weight.

They’ve also become something of a cultural phenomenon; in the last three months of 2022, US health-care providers wrote more than 9 million prescriptions for the drugs. Yet no one can explain precisely how and why they work. Part of the reason is that scientists still ­haven’t decoded the complex neural machinery involved in the control of appetite. 

“The drugs are producing the good effects, the satiety effects, through some aspect of this larger system,” says Lowell, who has watched their emergence with surprise and genuine fascination. “One of the most important components in figuring out how they work is to define what the system is. And that is what we are doing.” 

But the ultimate goal for Lowell and Andermann is far loftier than simply reverse-engineering the way hunger works.

The scientists are searching for the elusive bundle of neurons that allow our instinctual urge to eat to commandeer higher-­order brain structures involved in human motivation, decision-­making, memory, conscious thought, and action.

They believe identifying these neurons will make it possible to study how a simple basic impulse — in this case, a signal from the body that energy stores are beginning to run low and need to be replenished — propagates through the brain to dominate our conscious experience and turn into something far more complex: a series of complicated, often well-thought-out actions designed to get food.

This quest has so consumed Lowell in recent years that his graduate students have coined a term for the elusive bundle of brain cells he is seeking: “Holy Grail” neurons. 

It might sound like a tired scientific trope. But for the understated Lowell, the term is perfectly apt: what he’s seeking gets at the very heart of human will. Finding it would be the culmination of decades of work, and something he never imagined would become possible in his lifetime. 

The hunger mystery

Brad Lowell likes to joke that he is the token local at Beth Israel Deaconess Medical Center. Born in the hospital next door to where he now conducts research, he grew up 25 miles north in the town of Boxford and attended the University of Massachusetts, Amherst, a couple of hours’ drive away. 

Soon after arriving at UMass as an undergrad in the late 1970s, he was accepted into the physiological psychology lab of Richard Gold, a pioneering neuroscientist who was working to identify neural structures involved in regulating appetite. 

Gold’s focus was the hypothalamus — a primitive structure deep in the brain that hasn’t changed much through evolution. It is thought to be responsible for keeping the body in “homeostasis” by monitoring and balancing important functions like body temperature, blood pressure, our need for food and water, and other basic drives. 

Gold suspected that the paraventricular hypothalamic nucleus (PVH), a tiny patch of roughly 50,000 neurons in the hypothalamus, played a role in controlling appetite. By today’s standards, the tools to study it back then were “stone age” — Lowell says he used a “retracting wire knife” to sever bundles of neuronal projections that emanated from the PVH and connected to neurons outside it — but they were effective.

When the anesthetized rodents Lowell had operated on woke up, they were crazed with hunger, and they quickly became obese. 

The experience made a lasting impression. Lowell, then an athletic 19-year-old soccer aficionado, had always assumed that anyone who was overweight was just “lazy.” The experiment suggested there was likely far more to it than that. It also convinced Lowell to become a scientist. 

But further research into how precisely the brain worked to control hunger and satiety had reached something of an impasse. 

“Gold and a few other labs put the PVH on the map as a site required to restrain what you eat,” Lowell explains. “But they didn’t have the tools to look any further.”

Figuring out which of the 50,000 neurons in the PVH were actually important to appetite, the ones that could essentially mute the hunger switch, was a challenge that seemed insurmountable — akin to, as Lowell puts it, trying to untangle a “huge bowl of spaghetti.” 

“How do you differentiate one strand of spaghetti from another? These being neurons, right?” he asks. “There’s no way. They all look the same.”

When Lowell opened his own lab at Beth Israel Deaconess Medical Center in the early 1990s, after earning an MD and PhD at Boston University, he studied metabolism in tissues like muscle, organs, and fat that were connected to the brain through the peripheral nervous system. But his undergrad experience in Gold’s lab nagged at him.

“The brain is the Lord of the Rings,” Lowell says. “It’s the one ring that rules them all. And it was not that interesting to study these other things with the master player up there.” 

Chart titled, Mapping the hunger-satiety circuit: How do subconscious signals make it to the conscious part of the brain."  Part one shows the Hypothalamus containing the Hunger/satiety hormones, Leptin which excites satiety producing neurons, and Ghrelin which excites hunger producing neurons.  These neurons are both located within the Arcuate Nucleus and they inhibit each other. The melanocortin neurons that make up the PVH (paraventricular hypothalamic nucleus which acts as a Satiety Switch.  High activity in the PVH causes the feeling of satiety; low activity causes hunger.  In the second section is the Brain stem where the melanocortin neurons of the PVH have excited the "Holy Grail" neurons of the parabrachial nucleus, containing tens of thousands of unmapped neurons which also receives input from the gut and acts as a way station to higher-order brain areas.  Although much of this area remains unmapped, the area is thought to pass information to subcortical structures involved in emotioon and reward, eventually reaching the Cortex where we experience Conscious, Action-Oriented Activity.

The entry point

Early in his career, Lowell envied his colleagues who studied vision. For decades, neuroscientists had been able to trace the neural circuits involved in that function by shining light into the eyes of mice, identifying which neurons lit up, and then following them to map out the relevant brain circuits. Lowell and his peers who were interested in hunger had never had a similar entry point. 

That changed in 1994, when Jeffrey Friedman, a researcher at Rockefeller University, gave Lowell and others a way to identify the first important neurons — or individual “strands of spaghetti” — involved in hunger regulation. 

Back in 1949, scientists at the Jackson Laboratory in Bar Harbor, Maine, had bred mice with an unidentified genetic mutation that caused them to grow massively obese. They hypothesized that the obesity stemmed from the mice’s inability to produce a crucial protein involved in weight regulation.

Decades later, Friedman was the first to apply cutting-edge genetic technologies to clone the DNA sequences that were abnormal in the obese mice; he then confirmed that their obesity was caused by an inability to produce a key hormone released by fat cells, which the brain uses to track the body’s available energy stores.

Friedman purified the hormone and named it leptin. He also identified the DNA sequence needed to make the leptin “receptor” — the specialized proteins that stick out of brain cells involved in appetite regulation like microscopic antennae, sensing whenever leptin is present and kicking off a chemical cascade that promotes a sense of satiety. 

The discovery added further evidence to the idea that obesity was biologically determined, and more specifically to the concept of a “set point” when it comes to weight — a predetermined weight, fat mass, or other measurable physiological characteristic that the body will defend. Appetite is the means by which the body performs “error correction” and mobilizes to devote energy and attention to the task of restoring homeostasis. ….

MiT Technology Review: Read the full fascinating article here