“We live in unprecedented times, in which the overconsumption of fats and sugars is causing an epidemic of obesity and metabolic disorders,” said first author Mengtong Li, Ph.D., a postdoctoral researcher in the lab of the Zuckerman Institute’s Charles Zuker, Ph.D., supported by the Howard Hughes Medical Institute. “If we want to control our insatiable desire for fat, science is showing us that the key conduit driving these cravings is a connection between the gut and the brain.”
When the researchers were investigating the source of our appetites, a new connection between the gut and brain was discovered that drives our desire for fat, and according to the researchers, the discovery brings about questions regarding the possibility of interfering with this gut-brain connection to help curb unhealthy food choices in an attempt to help address the growing global health crisis caused by those choices and overeating.
During their studies, the researchers found that glucose activated a specific gut-brain circuit that communicates to the brain when in the presence of intestinal sugar. But this effect was not observed in the presence of calorie-free artificial sweeteners, which may explain why diet sodas never hit the spot and leave us feeling unsatisfied.
“Our research is showing that the tongue tells our brain what we like, such as things that taste sweet, salty or fatty,” said Dr. Zuker, who is also a professor of biochemistry and molecular biophysics and of neuroscience at Columbia’s Vagelos College of Physicians and Surgeons. “The gut, however, tells our brain what we want, what we need.”
To explore how mice respond to dietary fats, which must be consumed to provide the building blocks of life, the animals were fed bottles of water with dissolved fats and bottles of water containing sweet substances which are believed not to affect the gut but are initially appealing. Over a few days, the animals were observed to have developed strong preferences for fatty water. This preference remained even when mice were genetically altered to remove the ability to taste fat using their tongues.
“Even though the animals could not taste fat, they were nevertheless driven to consume it,” said Dr. Zuker.
The researchers hypothesized that the fat must be activating specific brain circuits that then drive the animal’s behavioral response to the fat. To test this theory and identify the circuit the researchers measured brain activity in the mice while feeding them fat. The researchers observed that neurons in one region of the brainstem called the caudal nucleus of the solitary tract (cNST) were more active, this is also interesting because cNST was also implicated in the previous discovery of the neural basis of sugar preference.
After finding this region, the researchers were then able to find the communication lines that carry the message to the cNST. These lines were neurons in the vagus nerve which links the gut to the brain, as they lit up with activity when the animals had fat in their intestines. Now that the biological mechanisms underlying the preference for fat had been identified, the researcher began to take a closer look at the gut, specifically endothelial cells lining the intestines. Two groups of cells were found to send signals to the vagal neurons in response to fat.
“One group of cells functions as a general sensor of essential nutrients, responding not only to fat, but also to sugars and amino acids,” said Dr. Li. “The other group responds to only fat, potentially helping the brain distinguish fats from other substances in the gut.”
Taking the investigation a step further toward possible interventions, the researchers attempted to block the activity of these cells with a drug. Shutting down the signaling from either group of cells prevented the vagal neurons from responding to fat in the intestines. Going another step further the researchers used genetic techniques to deactivate either the vagal neurons themselves or the neurons within the cNST, which in both cases caused the animals to lose their appetite for fat.
“These interventions verified that each of these biological steps from the gut to the brain is critical for an animal’s response to fat,” said Dr. Li. “These experiments also provide novel strategies for changing the brain’s response to fat and possibly behavior toward food.”
Unhealthy food cravings are a bigger issue than most understand, and the stakes are high as the rate of obesity has nearly doubled globally since 1980, what’s more, is that they keep increasing. In addition to the global epidemic of obesity, nearly a half billion people also suffer from diabetes.
“The overconsumption of cheap, highly processed foods rich in sugar and fat is having a devastating impact on human health, especially among people of low income and in communities of color,” said Dr. Zuker. “The better we understand how these foods hijack the biological machinery underlying taste and the gut-brain axis, the more opportunity we will have to intervene.”
“This exciting study offers insight about the molecules and cells that compel animals to desire fat,” said Scott Sternson, Ph.D., a professor of neuroscience at the University of California, San Diego, who was not involved in the new research when highlighting its potential for improving human health., whose work focuses on how the brain controls appetite. “The capability of researchers to control this desire may eventually lead to treatments that may help combat obesity by reducing consumption of high-calorie fatty foods.”
This research was supported in part by the Russell Berrie Foundation program in the neurobiology of obesity. Charles Zuker is an investigator of the Howard Hughes Medical Institute.
Competing interests: Charles Zuker is also a scientific co-founder and advisor of Kallyope, a biotech company developing a therapeutic platform based on our comprehensive understanding of gut-brain biology.
