New study blames diet cravings for fatty food on gut-brain connection

At Columbia’s Zuckerman Institute in New York, scientists studying mice found that fat entering the intestines triggers a signal. Conducted along nerves to the brain, this signal drives a craving for fatty foods. The new study raises the possibility of interfering with this gut-brain connection to help prevent unhealthy choices in an individual’s diet and address the growing global health crisis caused by overeating.

First author Mengtong Li, PhD, a postdoctoral researcher in the lab of the Zuckerman Institute’s Charles Zuker, PhD, supported by the Howard Hughes Medical Institute, said: “The overconsumption of fats and sugars is causing an epidemic of obesity and metabolic disorders. 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.”

Dieting: like versus want

This new view of dietary choices and health started with previous work from the Zuker lab on sugar. Researchers found that glucose activates a specific gut-brain circuit that communicates to the brain in the presence of intestinal sugar. Calorie-free artificial sweeteners, in contrast, do not have this effect, likely explaining why diet sodas can leave us feeling unsatisfied and craving more.

Zuker who is also a professor of biochemistry and molecular biophysics and of neuroscience at Columbia’s Vagelos College of Physicians and Surgeons, added: “Our research is showing that the tongue tells our brain what we like, such as things that taste sweet, salty or fatty. The gut, however, tells our brain what we want, what we need.”

Li wanted to explore how mice respond to dietary fats: the lipids and fatty acids that every animal must consume to provide the building blocks of life. She offered mice bottles of water with dissolved fats, including a component of soybean oil, and bottles of water containing sweet substances known to not affect the gut but that are initially attractive.

The rodents developed a strong preference, over a couple of days, for the fatty water. They formed this preference even when the scientists genetically modified the mice to remove the animals’ ability to taste fat using their tongues.

Specific brain circuits

The researchers reasoned that fat must be activating specific brain circuits driving the animals’ behavioural response to fat. To search for that circuit, Li measured brain activity in mice while giving the animals fat. Neurons in one particular region of the brainstem, the caudal nucleus of the solitary tract (cNST), perked up. This was intriguing because the cNST was also implicated in the lab’s previous discovery of the neural basis of sugar preference.

Li then found the communications lines that carried the message to the cNST. Neurons in the vagus nerve, which links the gut to the brain, also twittered with activity when mice had fat in their intestines.

Having identified the biological machinery underlying a mouse’s preference for fat, Li next took a close look at the gut itself: specifically, the endothelial cells lining the intestines. She found two groups of cells that sent signals to the vagal neurons in response to fat.

She said: “One group of cells functions as a general sensor of essential nutrients, responding not only to fat, but also to sugars and amino acids. The other group responds to only fat, potentially helping the brain distinguish fats from other substances in the gut.”

Li then went one important step further by blocking the activity of these cells using a drug. Shutting down signalling from either cell group prevented vagal neurons from responding to fat in the intestines. She then used genetic techniques to deactivate either the vagal neurons themselves or the neurons in the cNST. In both cases, a mouse lost its 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,” Li added. “These experiments also provide novel strategies for changing the brain’s response to fat and possibly behaviour toward food.”

The stakes are high. Obesity rates have nearly doubled worldwide since 1980. Today, nearly half a billion people suffer from diabetes.

The study is published in Nature.

Image: Vagal neurons that carry signals from the gut to the brain (nuclei shown in blue), with cells responsible for fat preference in green.

Credit: Mengtong Li/ Zuker lab/ Columbia’s Zuckerman Institute