At Columbia’s Zuckerman Institute, researchers studying mice found that fat entering the intestines triggers a signal. Conducted along the nerves to the brain, this signal drives a desire for fatty foods. Published September 7, 2022, in Nature, the new study raises the possibility of disrupting this gut-brain connection to help prevent unhealthy choices and address the growing global health crisis caused by overeating.

“We are living in unprecedented times where the overconsumption of fat and sugar is causing an epidemic of obesity and metabolic disorders,” said first author Mengtong Li, PhD, a postdoctoral fellow in the laboratory of the Zuckerman Institute’s Charles Zuker, PhD, supporter. of the Howard Hughes Medical Institute. “If we want to control our insatiable desire for fat, science shows us that the key channel that drives these cravings is a connection between the gut and the brain.”

This new view of dietary choices and health started with earlier 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 gut sugar. Calorie-free artificial sweeteners, on the other hand, do not have this effect, which likely explains why diet soda can leave us feeling unsatisfied.

“Our research shows 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. “However, the gut tells our brain what we want, what we need.”

Dr. Li wanted to explore how mice respond to dietary fat: 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 fat, including a soybean oil component, and bottles of water containing sweet substances known not to affect the gut but which are initially attractive. Over the course of a few days, the rodents developed a strong preference for the oily water. They formed this preference even when the researchers genetically modified the mice to remove the animals’ ability to taste fat using their tongues.

“Even though the animals couldn’t taste fat, they were still driven to consume it,” said Dr. Zucker.

The researchers reasoned that fat must activate specific brain circuits that drive the animals’ behavioral response to fat. To search for that circuit, Dr. Li brain activity in mice while feeding the animals fat. Neurons in a specific region of the brainstem, the caudal nucleus of the solitary tract (cNST), spiked. This was intriguing because the cNST was also implicated in the lab’s previous discovery of the neural basis of sugar preference.

Dr. Li then found the lines of communication that carried the message to the cNST. Neurons in the vagus nerve, which connects the gut to the brain, also chirped with activity when mice had fat in their guts.

After identifying the biological machinery underlying a mouse’s preference for fat, Dr. Next, take a closer look at the gut itself: specifically, the endothelial cells that line the intestines. She found two groups of cells that sent signals to the vagal neurons in response to fat.

“A group of cells acts as a general sensor for essential nutrients, responding not only to fat but also to sugars and amino acids,” said Dr. Lee. “The other group only responds to fat, potentially helping the brain distinguish fat from other substances in the gut.”

Dr. Li then went an important step further by blocking the activity of these cells using a drug. Shutting down signaling from both cell groups prevented vagal neurons from responding to fat in the gut. She then used genetic techniques to disable either the vagal neurons themselves or the neurons in the cNST. In both cases, a mouse lost its appetite for fat.

“These interventions confirmed that each of these biological steps from the gut to the brain is critical to an animal’s response to fat,” said Dr. Lee. “These experiments also provide new strategies for changing the brain’s response to fat and possibly behavior toward food.”

The stakes are high. Obesity has almost doubled worldwide since 1980. Today, almost half a billion people suffer from diabetes.

“The overconsumption of cheap, highly processed foods high in sugar and fat is having a devastating impact on human health, especially among low-income people and in communities of color,” said Dr. Zucker. “The better we understand how these foods hijack the biological machinery underlying taste and the gut-brain axis, the greater the opportunity we have to intervene.”

Scott Sternson, PhD, professor of neuroscience at the University of California, San Diego, who was not involved in the new research, highlighted its potential to improve human health.

“This exciting study provides insight into the molecules and cells that compel animals to desire fat,” said Dr. Sternson, whose work focuses on how the brain controls appetite. “Scientists’ ability to control this desire may ultimately lead to treatments that can help fight obesity by reducing the consumption of high-calorie, high-fat foods.”

The paper, titled “Gut-Brain Circuits for Fat Preference,” was published Sept. 7, 2022, in Nature. Its authors are Mengtong Li, Hwei-Ee Tan, Zhengyuan Lu, Katherine S. Tsang, Ashley J. Chung, and Charles S. Zuker.

This research was supported in part by the Russell Berrie Foundation Program in the Neurobiology of Obesity. Charles Zuker is an investigator at the Howard Hughes Medical Institute.

This story has been published from a wire agent feed with no changes to the text.

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