How Cysteine Depletion Drives Cells to Burn Fat

Historically, much of weight loss advice focused on eating less and moving more. In recent times, researchers discovered that what, and not just how much, someone eats also influences weight loss and metabolic health.

For instance, restricting the intake of certain amino acids—the building blocks of proteins—like cysteine and methionine improved metabolic health in both people and animal models.^1,2 However, researchers did not fully understand how depleting these molecules led to the beneficial effects.

Now, in a study published in Nature Metabolism, researchers found that depleting cysteine in mice converted fat-storing white adipose tissue into calorie-burning brown adipose tissue via the sympathetic nervous system, promoting weight loss.³ The results reveal signaling pathways that scientists could harness for metabolic disease therapeutics.

Amany Elshorbagy, a medical physiologist and visiting scientist at Oxford University who was not associated with the study, said, “It's a very strong piece of work, quite impressive, quite thorough” and significantly advances the field. Although researchers knew that cysteine plays a role in weight loss, “they have uncovered mechanisms that were worth looking at,” and provided compelling evidence, she added.

Study coauthor Lucie Orliaguet, a cell biologist in Vishwa Deep Dixit’s lab at the Yale School of Medicine, and her colleagues started by investigating the mechanism by which caloric restriction reduced weight in about 200 participants of a previously-conducted clinical trial.⁴ Profiling the metabolomes of their fat tissues revealed a rewired cysteine metabolism, prompting the researchers to identify the link between cysteine and weight loss.

To this end, they induced cysteine deficiency in mice by deleting a gene encoding an enzyme—cystathionine gamma-lyase (CTH)—required for cysteine synthesis and fed the mice a cysteine-free diet. Despite having appetites almost similar to control animals, cysteine-deficient mice lost almost 30 percent of their body weight in a week. When the researchers fed mice lacking CTH a high-fat diet, they became obese, but after they removed dietary cysteine from that high calorie diet, the mice lost weight.

“We were kind of expecting a weight loss,” said Orliaguet. “But what was very surprising for us was actually that the phenotype was very drastic and very quick.”

To better understand the dramatic effect, the researchers examined the animals’ adipose tissue and observed transformation of fat-storing white adipose depots into brown adipose tissue, which burns energy to generate heat. Restoring dietary cysteine in Cth-knockout mice reversed adipose browning and led to weight gain.

Previous reports indicated that the sympathetic nervous system, which regulates the body's unconscious actions, influences adipose browning via noradrenaline signaling through β3-adrenergic receptors in adipose tissue.⁵ To investigate whether similar players participated in cysteine deficiency-induced browning, Orliaguet and her team mapped the animals’ brain activity. They observed that, compared to controls, cysteine-deficient animals showed higher activation of brain regions involved in triggering the sympathetic nervous system.

Mass spectrometry of brown adipocytes revealed that cysteine starvation-induced browning increased the concentration of noradrenaline. Blocking β3-adrenergic receptors in cysteine-deficient mice prevented drastic weight loss and adipose browning, indicating that cysteine starvation triggers sympathetic nervous system-derived noradrenaline signaling via these receptors.

While the in vivo results are promising, Orliaguet noted it is not possible to cut out cysteine from the human body, which synthesizes the amino acid naturally and uses it as a precursor for important metabolites.

“The idea would be just maybe trying to find some like nutritional interventions that could just help us to lower the intake,” said Orliaguet. A vegetarian or vegan diet with reduced animal protein could help achieve this, but it is important to maintain enough cysteine to preserve vital functions, she cautioned.

Elshorbagy agreed, adding that researchers have long known that cysteine restriction causes weight loss in mice. “And the question is, how can you titrate that effect in humans to be sustainable and of metabolic benefit?” she said. Bridging this translational gap “is where I think our work needs to be directed next.”