It’s so hard to turn down just one more muffin, or cupcake, or cookie. Rodent studies reveal why: The mechanisms that control the hunger for and the pleasure from food are inextricably intertwined.
You’ve already had a muffin. And a half. You know you’re full. But there they are, fluffy and delicious, waiting for the passersby in the office. Just thinking about them makes your mouth water.
Maybe if you just slice one into quarters. I mean, that barely counts…
And then we give in, our brains overriding our body’s better judgment. When I catch myself once again polishing off a whole plate of baked goods, I wish that there was something I could do, some little pill I could take that would make that last delicious bite look — and taste — a little less appealing.
But the more scientists learn about the human body, the more they come to understand that there is no one set of hormones for hungry, with a separate set that kicks off your ice cream binge. Instead, our guts and their hormones are firmly entwined with our feelings of reward and motivation. That close relationship shows just how important it is to our bodies to keep us fed, and how hard it is to stop us from overeating.
Researchers have long divided our feeding behavior into two distinct categories. One, the homeostatic portion, is primarily concerned with making sure we’ve got enough energy to keep going and is localized to the lateral hypothalamus in the brain. The reward-related, or “hedonic,” component is centralized in the mesolimbic dopamine system, areas of the brain usually referenced when we talk about the effects of sex, drugs and rock ’n’ roll.
When many of us think about what controls appetite, insulin, ghrelin and leptin come to mind. All of these hormones are involved in whether we feel hungry or not. Insulin, released from the pancreas as we take in and digest food, helps us put down the fork. Leptin, released from fat cells, similarly contributes to helping us feel full. Ghrelin, on the other hand, is produced in the gastrointestinal tract when the stomach is empty, and increases as we get closer to our next meal, contributing to feelings of hunger.
Other chemical messengers are tied to the homeostatic parts of hunger, and are also associated with the reward-related aspects of eating. Glucagon-like peptide-1, released from a small set of brain cells in the brain stem, stops subjects from eating high-fat food specifically. Similarly, the brain’s native cannabinoid system can promote eating when stimulated, and reduce it when suppressed (the plant-based cannabinoids stimulate this system, for anyone who has ever heard of “the munchies”). Orexin, a chemical released from the hypothalamus, also increases the amount that animals eat.
But scientists can’t distinguish energy-related eating from pleasure-fueled feeding that easily. All of these chemicals (and many more) converge on the same region of the brain, the mesolimbic dopamine system. Dopamine is associated with feelings of pleasure and reward, but it’s also connected with something called salience, or whether something is prominent or important enough to pay attention to and then remember. “If the dopamine system is not implicated in a behavior…then it will not happen,” says Roger Adan, a molecular neuroscientist at the University Medical Center Utrecht in the Netherlands. “It’s good to have a system that’s rewarding. This is an innate response.” The dopamine system, he says, gives us the jolt of salience that helps us focus on getting when the getting is good.
The need capitalize on opportunity means that sometimes, the reward-centered side will need to take priority over energy needs. You may not need food right this minute, but you’ll need to learn and remember where those tasty apples are. And so the energy-balancing hypothalamus and the mesolimbic dopamine system have become very well connected. “The circuitry is completely intertwined,” says Zhiping Pang, a synaptic physiologist at Rutgers University in New Brunswick, N.J. “It’s very difficult to tease them apart.”
Ghrelin and leptin both have receptors in the area of the brain where dopamine cell bodies are located. Leptin can decrease dopamine cell firing in this area, reducing an animal’s sensitivity to food cues, Adan and colleagues reported July 17 in the International Journal of Obesity. Conversely, ghrelin increases an animal’s sensitivity to food cues by increasing dopamine responses in the mesolimbic system, Mitchell Roitman, a behavioral neuroscientist at the University of Illinois in Chicago, and his colleagues reported in March in the Journal of Neurochemistry.
The hormones from the periphery are far from alone. Pang and his colleagues recently showed that glucagon-like peptide-1 acts via the dopamine system to suppress high-fat (and therefore tasty) food intake in mice. They published their results August 4 in Cell Reports.
Orexin, though produced in the hypothalamus, is also heavily involved with dopamine. “It seems to be a bridge between the homeostatic and the hedonic systems,” says Mario Perello, a neuroendocrinologist at the Multidisciplinary Institute of Cell biology in La Plata, Argentina. His group has found that orexin-producing neurons are activated when mice eat a high-fat diet, but ghrelin is required to go from simple feeding to binge-eating the fatty food, the researchers report in the October Psychoneuroendocrinology.
Leptin and ghrelin, arbiters of fullness and hunger, affect cells in the brain that produce dopamine — that chemical messenger so often associated with reward — but so do the hormones from the hypothalamus. Some of the hormones from the hypothalamus may also modulate the effects of leptin and ghrelin.
So amidst these crossing signals, it’s hard to choose a single target for a drug that could control appetite, let alone the eating we do when we’re not actually hungry. All the molecular roads may lead to dopamine, but attacking dopamine itself is, unfortunately, out of the question. It’s true that cutting out the mesolimbic dopamine system entirely reduces an animal’s motivation for food. But it also cuts out everything else. “You take out the dopamine system and you wipe out reward,” says Peter Kalivas, a neuroscientist at the Medical University of South Carolina in Charleston. “It’s too close to the root of human behavior.”
A lesson can be found in the story of rimonabant, a cannabinoid receptor antagonist that was approved in Europe in 2006 for the treatment of obesity. It suppresses the dopamine system, and with it, food intake. “It resulted in weight loss,” says Adan. “But it also made people depressed. It wasn’t specific enough.” Rimanobant was withdrawn from the market in 2009 for fears over side effects, including psychiatric effects.
Other chemicals show more promise for reducing overeating without quite as many side effects. Drugs that stimulate glucagon-like peptide-1 have been previously approved for type 2 diabetes, and in December 2014 one of these, Saxenda, was also approved for obesity treatment. Within the brain, glucagon-like peptide-1 is “only secreted from a very small group of neurons in the brain stem,” says Pang. “It’s only one group of neurons so it’s easier to tackle.”
All of that research illustrates that it’s not accurate to put some hormones in a hunger bucket and others in a box for reward. “I think we’re going to be focusing less on that difference in the future,” says Stephanie Borgland, a neuroscientist at the University of Calgary in Alberta, Canada, who published a review in March of more than 15 chemicals that interact with the dopamine system. “When you’re hungry the reward system is influenced, you’re in a negative reward state and you eat to overcome that negative reward,” She says. “In my opinion the two don’t happen independently.”
So while a muffin-resistance pill is probably never in our future, a greater understanding about how food intake works is. But unfortunately, knowledge is only half the battle. “Every morning I go get a cup of coffee from the campus café, and most mornings I wind up failing to resist the lure of the chocolate chip muffin,” Roitman says ruefully. His greater understanding of why and how get the snackies, he says, “doesn’t make it easier.” Understanding the many chemical signals behind when and why we eat might take us halfway there, but we’ll have to apply that knowledge to changing our habits for the best chance at leaving the muffins alone.
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