Dissecting Hunger and Food Cravings

One of the greatest challenges facing anyone trying to lose weight is our world of seemingly endless temptations: Burgers, pizza and doughnuts beckon from highway billboards, TV and radio ads invite us to “supersize,” and a mouth-watering variety of candy bars are on display at the supermarket checkout counter.

When our stomachs are growling, avoiding these tempting messages can seem virtually impossible.

It turns out that whether we pull up to the fast-food drive-up window or toss the candy bar in our grocery shopping cart is more than just a matter of willpower.

As BIDMC neuroscientists Mark Andermann, PhD , and Bradford Lowell, MD, PhD , are discovering, hunger and cravings likely arise from the communication between complex neural circuits in the brain. Their research, which focuses on untangling the brain pathways responsible for these motivations, holds promise for the development of drug therapies for the treatment of obesity or loss of appetite.

Underlying Motivations

Andermann is using new technologies to bring to light how brain cells process images of food and other “environmental cues.” His studies in animal models are revealing how cells in various brain regions change their activity depending on whether the mouse has been fed.

“I want to understand how the brain’s cortex — the region that imagines, feels, senses, perceives and decides where to direct attention — is driven by the basic needs of the stomach,” says Andermann (right), an investigator in BIDMC’s Division of Endocrinology, Diabetes and Metabolism who was recently awarded a prestigious $1.5 million grant from the National Institutes of Health (NIH) to support this work.

“For example, what’s happening when you are driving along and you start to pay less attention to other cars and more attention to roadside restaurants? I think a better understanding of the brain circuits involved in these processes might lead to novel insights into how to tackle the epidemic of obesity,” he adds.

Andermann has helped develop methods for imaging the activity of the same neurons across motivational states (such as hunger) by using two-photon imaging, a sophisticated technique based on principles of quantum physics. Through this technology, researchers can watch entire networks of neurons in a living mouse over the course of weeks, and can observe which neurons are activated by pictures that the animal has previously associated with the availability of a milkshake both prior to and following consumption of a meal. This helps explain how brain activity gradually changes as motivational states change.

“This is critically important in our current society, in which we are constantly bombarded with environmental cues that stimulate our appetites,” says Andermann. “This kind of brain activity can likely give rise to specific mental imagery [for example, when you imagine opening a candy wrapper] which, in turn, can have a powerful influence over a person’s future actions, including consuming unhealthy foods.”

The Hunger Games

At the same time, Lowell has been studying the brain’s “hunger” neurocircuits and is creating a “wiring diagram” of the complicated jumble of brain pathways and chemicals that underlie this intense motivational state.

“Abnormal hunger can lead to obesity and eating disorders, but in order to understand what might be wrong — and how to treat it — you first need to know how it works,” says Lowell (right), also an investigator in the Division of Endocrinology, Diabetes and Metabolism. “Otherwise, it’s like trying to fix a car without knowing how the engine operates.”

Lowell’s work focuses on the brain’s hypothalamus, the region that functions as the nerve center for feeding behavior. The hypothalamus contains at least a dozen different nuclei (clusters of many different types of neurons) and receives and emits a variety of signals for hunger and satiety (fullness).

“The hypothalamus is where cues from the stomach, intestines and body fat are received. These signals then converge with sensory data including sights, smells and tastes, and other motivational triggers,” says Lowell. “It’s a tangle of brain circuits that look like a Jackson Pollack painting.”

Through intricate studies in mice, Lowell is carefully untangling and dissecting all of this circuitry. Key among his findings has been the discovery that stimulating a group of nerve cells called the Agouti-related peptide (AGRP) expressing neurons causes mice to embark on a relentless search for food — and then to eat voraciously once they find the food. His research continues to reveal new clues about exactly how the AgRP neurons are activated and how they produce hunger.

“We are getting closer and closer to completing our wiring diagram — and our understanding of the consequences of abnormal hunger,” says Lowell.