Managing Editor—Science, Research, and Education at Yale School of Medicine.

Mallory Locklear, PhD

Eating a high-fat diet will typically result in weight gain. But a new study published in 

 has uncovered an unexpected biological loophole that turns fat storage into fat usage.

In the study, mice became obese when consuming high-fat food, as expected. But when Yale researchers removed an amino acid called cysteine from the animals’ diets and blocked their ability to produce it internally, the obese mice returned to a healthy weight with reduced inflammation—all while continuing to consume the same amount of high-fat food.

The researchers found that this effect was driven by a dramatic shift in the fat tissue of the mice: Once the cysteine was removed from their diet nearly all of the white fat—the kind that stores energy—was converted to brown fat, which dissipates energy as heat, a process known as “browning.” The mice were essentially burning off the extra calories as they were consumed.

We have what appear to be endogenous protective mechanisms that are no longer active based on our lifestyles. But they can be reactivated.
Vishwa Deep Dixit, DVM, PhD

The findings reveal that depletion of just one amino acid in an otherwise normal diet turns on a switch that burns fat without breaking down muscle mass, and they offer clues as to how this might be harnessed to improve health and longevity in humans.

“All of these findings were completely unexpected. And when that happens in science, it’s tremendously exciting,” says 

, senior author of the study, Waldemar Von Zedtwitz Professor of Pathology, Immunobiology, and Comparative Medicine at Yale School of Medicine, and the director of Yale Center for Research on Aging.

Moderately reducing calorie intake lowers cysteine

Cysteine emerged as an intriguing molecule for human longevity through the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE-II) clinical trial, the first controlled study of calorie restriction in healthy humans. A portion of the trial’s participants reduced their total food consumption, lowering their regular calorie intake by around 15% for two years. Researchers then assessed the long-term health effects.

Overall, the trial revealed that this moderate calorie restriction significantly reduced a number of cardiovascular and metabolic risk factors, leading to improved health. Since the trial’s completion, researchers have been investigating 

; among their discoveries was that a metabolic pathway that regulates how much cysteine is available in the body behaved differently in the participants who reduced their calorie intake.

These findings—the substantial benefits of moderate calorie restriction and everything we’ve discovered since—wouldn’t have been possible without the CALERIE-II trial. This was a multi-center trial funded by the National Institutes of Health and without that support, we would still be in dark as to what these critical metabolic pathways are in terms of regulating weight and maintaining health, things we’ll be able to harness in the future as we learn more.
Vishwa Deep Dixit, DVM, PhD

For the new study, Dixit and his colleagues dug further into this finding, measuring thousands of metabolites and amino acid levels in the fat tissue of CALERIE-II participants. They found that those who reduced their calorie intake had lower levels of cysteine and a reprogrammed metabolic system.

“So then we wanted to understand whether cysteine was driving some of the beneficial effects calorie restriction had on the immune system, inflammation, and metabolism,” says Dixit.

To do that, they turned to an animal model, through which they observed that cysteine deprivation causes this fundamental shift in fat tissue.

“What we found in the mice was that cysteine deprivation converted white fat into brown fat,” says Dixit. “It wasn’t just a little bit here and there. It was a dramatic transformation.”

Brown fat generates heat, which we don’t need in the modern world as much of our life is spent in largely temperature-regulated environments. But this is a critical evolutionary protective mechanism, because if our core body temperature falls even three or four degrees below its norm, that can be fatal.

This is true for all warm-blooded animals, so brown fat that produces heat by burning fat is designed for our survival.

The researchers discovered that completely removing cysteine from the body accelerated fat burning—essentially removing the brakes from metabolism. This finding, the researchers say, opens the door for controlled cysteine-restriction as a potential dietary approach to enhance health and lifespan by reducing excess fat.

Signals from the brain control changes in fat

To better understand this dramatic change, the researchers measured brain activation, looking for any areas that were more or less active than usual when there was no access to cysteine. They found several regions that were overly active, all of which were involved in triggering the sympathetic nervous system, which regulates much of our bodily processes that aren’t under our conscious control, including body temperature and metabolism.

“I wish metabolism was under our conscious control, but it’s not,” says Dixit.

The nerves of the sympathetic nervous system, once activated, released a chemical called norepinephrine into the fat tissue, which then induced the flip from white to brown fat, the researchers found. When they blocked the receptor for norepinephrine, this browning stopped, halting the fat loss.

The researchers are continuing to investigate this role of cysteine, aiming to identify how mitochondria in fat cells are triggered to generate heat rather than the energy molecules they typically produce.

“We think that cysteine is very critical for the metabolic benefits of food restriction and that it actually drives fat loss by inducing this temperature regulation process,” says Dixit.

Removing cysteine entirely is essential for understanding its role, but it’s not representative of what would happen in the real world. However, evidence suggests 

 in cysteine intake also have physiological effects that seem to be largely beneficial.

For example, other researchers have found that restricting cysteine and a similar amino acid called methionine just from the diet causes mice to live up to 50% longer, and in people, causes weight loss and improves metabolic health. And this may be in part due to how the body responds to a drop in cysteine.

“There’s a pathway in the body that can make cysteine,” says Dixit. “During abundance it’s normally dormant but if you’re getting less cysteine from your diet, your body activates this pathway in an effort to make more. And it appears that awakening this dormant pathway produces metabolic and health benefits.”

In the CALERIE-II study, participants were reducing calorie intake across the board, eating less of all types of food components, including protein. And while they had less cysteine in their fat tissue, that usually dormant cysteine-producing pathway was activated in these participants.

“We have what appear to be endogenous protective mechanisms that are no longer active based on our lifestyles,” says Dixit. “But they can be reactivated.

“These findings—the substantial benefits of moderate calorie restriction and everything we’ve discovered since—wouldn’t have been possible without the CALERIE-II trial,” he adds. “This was a multi-center trial funded by the National Institutes of Health and without that support, we would still be in dark as to what these critical metabolic pathways are in terms of regulating weight and maintaining health, things we’ll be able to harness in the future as we learn more.”

The research reported in this news article was supported by the National Institutes of Health (awards AG031797, AG073969, AG068863, and P01AG051459) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Articles

A recent study reveals that removing cysteine from the diet of mice consuming high-fat food leads to weight loss and reduced inflammation by converting white fat to brown fat, which burns energy as heat. This discovery suggests that cysteine depletion could be a potential strategy for enhancing health and longevity. The CALERIE-II trial showed that moderate calorie restriction in humans lowers cysteine levels, activating metabolic pathways that promote health benefits. These findings highlight the potential of dietary interventions targeting cysteine to improve metabolic health and longevity.

A new study reveals how removing cysteine from diets transforms fat storage into fat burning, offering insights for improved health and longevity.