Jan. 26, 2024 – The cravings feel inevitable and unavoidable – you stand up, walk to the kitchen, open the fridge or pantry, and ponder. Although you remind yourself to consider a piece of fruit or some protein, your eyes linger on the potato chips and cookies.
If fats and sugars sometimes seem irresistible, you’re not alone. A new study published in Cell Metabolism, based on work by researchers at the Monell Chemical Senses Center in Philadelphia, shows we have two separate but parallel fat and sugar craving pathways that send signals from the gut to the brain, which light up our dopamine reward centers. Even more so, combining these pathways appears to trigger our desire to eat more than usual.
“Over the past few years, we have developed new tools to study the vagus nerve as a pathway of communication between the gut and the brain to control food intake. In this study, we used these tools to understand a simple question that we feel is at the center of the obesity epidemic: Why do we eat foods that we know are bad for us?” said study author Guillaume de Lartigue, PhD, a neuroscientist at Monell who studies the neurobiology of eating.
Specifically, the vagus nerve sends internal sensory information through nerve cells in the gut – rather than taste cells in the mouth – which plays a key role in making fats and sugars appealing. Ultimately, the research may indicate what controls “motivated” eating behavior and how a subconscious desire to eat fats and sugars can counteract dieting efforts.
“We propose that this gut mechanism helps explain, at least in part, why we overeat foods that are rich in fats and sugars,” de Lartigue said. “This provides insight into the cause of overeating and why dieting is so hard. We are literally having to fight the subconscious drive to eat that doughnut.”
Understanding the Gut-Brain Dynamic
De Lartigue and colleagues used new cutting-edge neuroscience technology to directly manipulate fat or sugar neurons in the vagus nerve system of mice. They found that both types of neurons cause a dopamine release in the brain’s reward center. They also discovered two dedicated vagus nerve pathways – one for fats and one for sugars – that start in the gut and send information about what has been eaten to the brain. This sets the stage for cravings.
After that, to understand how fats and sugars affect the brain, the researchers stimulated gut vagal nerves with light. This led the mice to actively seek food to engage these circuits, which demonstrated that fat and sugar are sensed by separate neurons and engage distinct reward circuits, which reinforces cravings.
On top of that, the research team found that activating both the fat and sugar circuits created a synergy, like a “one-two punch to the brain,” de Lartigue said. Combining fat and sugar led to significantly more dopamine release, which ultimately led to overeating in the mice.
Although the results need to be studied more in mice, as well as in humans, the findings are significant for current weight-related research, as well as treatments such as semaglutide and tirzepatide, which fall under a class of medications known as glucagon-like peptide-1 (GLP-1) receptor agonists and are sold under brand names such as Ozempic, Wegovy, and Mounjaro.
“The role of signals from the gut in the control of food intake has a long history, and the most powerful therapies to curb appetite and reduce body weight currently available (GLP-1 agonists and gastric bypass surgery) are based on changing such signals,” said Hans-Rudolf Berthoud, PhD, a professor of neurobiology and nutrition at the Pennington Biomedical Research Center at Louisiana State University.
“The sugar-fat combination is a particularly strong appetite driver in mice and may also explain diet-induced obesity in humans,” he said. “Learning more about gut-brain communication may eventually lead to the development of new and more specific therapies to combat obesity and its many complications.”
What Does This Mean for Your Gut?
These separate but parallel fat and sugar circuits may shed light on why dieting can be so challenging, de Lartigue said. Human brains likely seek out high-fat, high-sugar combinations, regardless of conscious efforts to cut back. Since these gut-brain communications occur below the level of consciousness, he noted, you may crave these foods without realizing it.
“The most immediate next question is to understand if inactivating these pathways could prevent animals or humans from having a preference for high-fat, high-sugar foods,” said Nicholas Betley, PhD, an associate professor of biology at the University of Pennsylvania.
“This is a difficult experiment because these cells are likely involved in the detection of other signals in the body, but if these pathways could be inactivated, you would expect that cake and ice cream after dinner would not be so appealing,” he said. “Of course, this is aspirational right now but would be the direction these findings could lead us.”
If the pathways could be controlled with drugs, then some medications could target consumption of sugary and fatty foods, he said. Future research could also potentially open doors to treatment for pathological behaviors such as binge eating, overeating, and anorexia.
“The dopamine pathways can also be used to promote healthy behaviors,” Betley said. “We have recently published on the effects of exercise on dopamine levels, suggesting that increasing exercise can change your microbiome and increase the dopamine surge you get from exercising. So these gut-brain communication pathways could be used to also reinforce healthy behaviors – and that our body is wired to allow for this as well.”
What Does This Mean for Your Brain?
Targeting and regulating gut-brain reward circuits could offer a novel approach to curb unhealthy eating habits. Ultimately, understanding the wiring behind your motivation to eat fats and sugars is the first step toward rewiring it, de Lartigue said. Even when faced with a tempting treat, people could make healthier choices based on personalized intervention plans.
“It’s becoming more and more apparent that these mechanisms play a big role in guiding eating behavior and food choice. Given the success of gut-derived peptides (such as Wegovy and Ozempic) for weight loss, it’s essential to understand the gut-brain axis to develop more effective treatments and strategies for weight loss and weight maintenance,” said Alexandra DiFeliceantonio, PhD, a neuroscientist and assistant professor at the Fralin Biomedical Research Institute at Virginia Tech Carilion.
“Most foods high in sugar and fat are highly processed or ultra-processed foods, and those combinations rarely occur in nature,” she said. “Our lab is working on understanding what other properties of processed and ultra-processed foods make them so irresistible.”
These neural pathways may also offer new insights into mental health and targeted treatments for brain health.
“Gut-to-brain signaling is not only critical for controlling metabolism and food intake, but recent emerging findings indicate an important role for the gut in cognition and brain health as well,” said Scott Kanoski, PhD, co-director of the University of Southern California’s Diabetes and Obesity Research Institute and president of the Society for the Study of Ingestive Behavior.
“We have recently identified a role for the vagus nerve in promoting learning and memory function,” he said. “Meals are important events to encode into memory, as such memories will guide more efficient foraging and consumption strategies in the future.”
In other words, sugar and fat cues may engage distinct circuitry in memory systems in the brain. More research could show whether behavioral changes or drugs could aid overall health as well.
“There has been a surprising amount of evidence showing how the brain and body rapidly communicate to influence our behavior – this tells us that our overall health and mental health are influenced by what we consume, how we treat our bodies, whether we exercise,” Betley said. “It really brings back the importance of holistic medicine as being important for our overall well-being, as this communication between our brain and our body likely impacts all aspects of our health. And while all these studies will enable the better production of drugs for a specific disorder, eating healthy foods and taking care of our body may be just as important for avoiding disorders and disease.”
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