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Our Urge To Eat Fatty Foods Is Caused by a Gut-Brain Signal

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The temptation of a burger or pizza has surprisingly little to do with our taste buds, finds a new study. Instead, connections between our gut and brain dictate our obsession for fatty foods, say the authors.

Sweet sensation

Six months ago, a study from researchers at Duke University found that mice lacking the ability to taste were still able to discern between sugar and artificial sweeteners. This might sound surprising but was built on years of research in a field that involves investigating the complicated connections between our mouth, gut and brain.

Professor Charles Zuker’s lab at Columbia University have been at the forefront of this research. In 2020, they published a paper mapping out the basic circuit that enables our gut to detect sugar without any help from our taste buds. Now, the same team has mapped out a mirror circuit that does the same job for fatty foods.

“We have shown that fats use the gut-brain axis to drive the strong appetite for fatty stimuli, and demonstrated they use totally different receptors and neuronal elements from sugar,” said first author Dr. Mengtong Li.

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

The research comes at a time when controlling intake of fatty foods has become a key goal of much public health messaging. “We are facing unprecedented challenges in human health, with over-nutrition taking center stage in our battle against obesity and metabolic disorders,” Li said.

Tracing the brain’s fat obsession

Li and Zuker’s study involved a complicated series of experiments that began with a group of mice offered, essentially, a free bar. Given the choice between a solution of artificially sweetened water and fat-infused water, the mice initially drank from both options. But within two days, the mice switched to exclusively drinking fatty water. Even when presented with a sugar drink that matched the fat drink for calorie content, the mice repeatedly came back to the latter option.

Perhaps mice just love the delicious taste of fat water? Li and Zuker hypothesized that the driving force for this behavior was south of the mouth. They tested mice that had been genetically modified to lack a taste receptor called TRPM5 that controls mouth to brain signaling in response to fat. Despite being unable to taste fat, the mice still relentlessly sought it out after a short period of time.

Following this neurochemical lead through the mice’s nervous systems, the team identified that fat, but not control substances, activated a population of neurons in the mice’s brainstems in a region called the caudal nucleus of the solitary tract (cNST). This was the same region where Zuker and colleagues had identified sugar sensing cells two years earlier. The cNST, importantly, does not receive signals from the mouth, but rather from the gut. Mice with genetically blocked cNST neurons no longer showed a long-term preference for fat.

The team then traced the pathway that fat signals activate in the brain in reverse. They showed that the vagus nerve, an important highway in the gut-brain axis, was responsible for transporting the messages. The team identified two distinct groups of vagal neurons:

  • Neurons that responded to three essential micronutrients in the gut: sugar, proteins and fats
  • Neurons that selectively responded to fat

Fat signals’ home in the gut

The team then closed the loop by showing that cells in the intestine called enteroendocrine cells (EECs) were responsible for sensing fat signals in the gut. Again, this is a biological approach shared by sugar-sensing pathways. But through a series of experiments used genetically modified mice, Li and Zuker revealed that while sugar-sensing EECs rely on a receptor called the sodium–glucose-linked transporter-1 (SGLT1), two separate proteins, GPR40 and GPR120, together help EECs receive fatty signals and send them up the vagus nerve channel.  

The findings, while at an early, pre-clinical stage, could prove an important first step in our understanding of how the drive for fatty foods begins at a cellular level. “Now we know the neural mechanisms that drive our insatiable appetite for fat, in principle, we can interfere with this gut-to-brain circuit to help manage our desire for fatty foods,” said Li. “The discovery of this circuit provides a path to develop new strategies and we are thrilled to contribute to such an important and timely problem.”

Liking and wanting

Zuker and Li were, however, keen to point out that a hypothetical person lacking GPR40 and GPR120 might well still delight in the taste of those burgers and pizzas. The study has exposed the separation between the foods we find tasty and those that motivate us to eat them. Often, these are inextricably linked, but these new experiments show there are important differences. The findings, write the authors in their paper, “clarify the fundamental difference between ‘liking’ and ‘wanting’”.

If that sounds confusing, Zuker offered an explanation. When it comes to food, “liking is what we enjoy … wanting is what we must have,” he concludes.


Li M, Tan H, Lu Z, Tsand KS, Chung AJ and Zuker CS. Gut-brain circuits for fat preference. Nature. 2022. doi: 10.1038/s41586-022-05266-z