Scientists Discover Brain–Fat Link That Controls Metabolism — And How to Hack It

When the researchers deleted only Piezo2 in the mice’s fat-sensing neurons — leaving the rest of the nervous system intact — the mice remained lean and metabolically resilient.

By Pesach Benson, TPS

In a breakthrough that fundamentally changes science’s understanding of how the body regulates fat and energy, an Israeli study has uncovered how the nervous system senses fat within the body — and how disabling that sense may protect against obesity, diabetes, and fatty liver disease.

Researchers at the Weizmann Institute of Science discovered that certain nerve cells detect mechanical changes — like pressure and tension — within fat tissue, and that suppressing this “fat sense” has profound effects on metabolism.

Mice engineered to lack these sensory neurons were able to stay lean and metabolically healthy even on a high-fat diet, despite eating the same amount and being less physically active than control mice.

The findings were recently published in the peer-reviewed journal Cell Metabolism, and are among the Weizmann Institute’s last published studies since the Rehovot campus was devastated by an Iranian ballistic missile on June 19.

A building containing the institute’s life sciences laboratory, including DNA and tissue samples, laboratory mice, computers, lab equipment and more was destroyed along with a second empty building that was to contain chemistry labs. Several other buildings were damaged.

“We tend to think of senses as something that helps us understand the outside world, but many of them monitor what’s happening inside the body,” said Prof. Elazar Seltzer, who led the study.

“It’s hard to grasp that, like muscles and the skeleton, we also sense the fat tissue in our bodies and change our energy utilization accordingly, but that’s exactly what we showed in mice.”

The research focused on different types of adipose tissue: white fat, which stores energy and is associated with obesity and metabolic disease; brown fat, which burns calories to generate heat; and beige fat, which behaves like brown fat when activated.

Until now, scientists knew that the nervous system could stimulate brown fat in response to cold or stress, but what kept it inactive under normal conditions remained unclear.

Dr. Fabian Pesini, the study’s lead author from Seltzer’s lab in the Department of Molecular Genetics, developed a mouse model lacking the neurons that detect mechanical signals in fat tissue.

“While breeding the engineered mice, we noticed that they gained less fat, even though they ate the same food and even moved less than the mice in the control group,” Pesini said.

“We tested them and detected a decrease in fat percentage, low blood sugar levels, and high sensitivity to insulin—their metabolic indices were such that every person would wish for.”

The key to this internal sensing system lies in a protein called Piezo2, a mechanical sensor used by neurons to detect pressure and stretch.

When the researchers deleted only Piezo2 in the mice’s fat-sensing neurons — leaving the rest of the nervous system intact — the mice remained lean and metabolically resilient.

They were even protected from fatty liver disease and insulin resistance after months on a high-fat diet.

“Until now, we have known the gas pedal of the nervous system that is responsible for activating brown and beige fat,” said Seltzer.

“But at the end of the day, as we know, we accumulate fat and do not burn all the energy reserves we have, so it was clear that there should also be a brake pedal that suppresses metabolism. In the new study, we showed that the brake pedal is actually nerve cells with the Piezo2 sensor that monitor mechanical changes in brown and beige fat.”

Though the researchers are still investigating what exactly these nerve cells are sensing — possibly changes in the stiffness or expansion of fat tissue — the implications are significant.

Neural feedback from fat appears to rapidly influence how much energy the body burns, independently of hormones like leptin, which have been the focus of most previous obesity research.

“More than half (54%) of the adult population in OECD countries is overweight or obese, and if we better understand the cells that sense fat tissue, we can try to influence them in a way that will help deal with obesity and the associated morbidity,” Seltzer said.

Given that 10 to 15 percent of daily energy is used just to maintain body temperature, even small shifts in fat tissue activity could have a major impact on overall metabolism.

Targeting the fat-sensing nerve cells or the Piezo2 sensor they use could lead to novel drugs that increase fat-burning by mimicking or blocking these internal signals.

Since disabling this fat-sensing pathway also prevented insulin resistance and fatty liver in mice, similar interventions might be used to treat or prevent type 2 diabetes and nonalcoholic fatty liver disease.