Obesity: Cysteine plays a key role: Amino acid may be at root of obesity

"There is a very high correlation between high levels of cysteine and obesity," explains Professor of Nutrition Helga Refsum of the University of Oslo's Department of Nutrition. The question is whether this is a causal relationship. Is much of the body's fat due to a high cysteine level, and if so, what is the connection? Why do some people have higher cysteine levels than others? How much is owing to genetic factors, and how much is affected by diet?

Researchers are now closing in on some answers. A comprehensive study, funded under the Research Council of Norway's funding scheme for independent basic research (FRIPRO), aims to shed light on the underlying biological mechanism linking cysteine to obesity. The project started up in 2010 and will run until 2013.

Cooperation between Oslo and Oxford

As an outstanding young researcher in Norway in 1998, Helga Refsum was awarded a grant which she used to build up a working relationship with Oxford University and Dr. Amany Elshorbagy. Their collaboration led to the discovery of a connection between cysteine and obesity.

The project has evolved into a close collaboration between the University of Oslo and Oxford University, involving several other research institutions as well.

Affects more than weight

Obesity is caused by the intake of more calories than are burned; any surplus is stored as fat in the body. The concept is a simple one at the general level. But at the molecular level, many more facets to this relationship emerge, making it more difficult to pin down. The long, complex biochemical processes of enzymes converting food to energy and building blocks can be affected by many factors. The same is true for the breakdown of fat.

Professor Refsum's research indicates that cysteine plays a key role in how the body metabolises energy, stores fat, and breaks down fat. In this latest project, the researchers will also study how cysteine affects the brain -- for instance, whether cysteine can influence the feeling of being satiated.

Blame our genes

Our genes play a large part in determining our weight.

"We know there is a strong genetic component to the body's weight and fat content," says Professor Refsum, pointing out that 50-80 per cent of body weight is due to genetic factors. "Look at the difference between males and females! Women always have more body fat than men. Nature intended it this way; this is how it should be."

Body fat percentage varies widely between ethnic groups. Taking these differences into account, health personnel tailor their body mass index (BMI) criteria for obesity to different populations.

Genetic factors are undoubtedly involved in cysteine levels, the professor stresses. Indeed, two known genetic conditions demonstrate a clear relationship.

People with the most common form of a genetic condition known as homocystinuria lack one of the enzymes that convert homocysteine to cysteine. These people have low cysteine levels and are extremely slender. By contrast, people with a different genetic condition, Down's syndrome, have 50% more of that same enzyme than normal- and they also have higher-than-average cysteine levels and tend to be overweight.

Public health focus

The connection between cysteine and obesity-related diseases is a major topic of Professor Refsum's research.

"We particularly want to find out if cysteine is associated with obesity-related morbidity -- the myriad of diseases such as diabetes, cardiovascular diseases and certain types of cancer that are associated with obesity. From a public health perspective, it is this aspect of obesity we need to worry about.

With lowered cysteine, mice shed fat

Professor Refsum and her colleagues have demonstrated that reducing cysteine levels leads to weight loss in mice and rats. With subsequent supplements of cysteine, the weight returns -- along with a higher risk of diabetes.

The researchers are now investigating the entire, complex chain of chemical reactions during metabolism, from ingesting food to cysteine functions. Cysteine is clearly related to weight, but what determines cysteine levels? Where does it all begin?

"Our experiments with mice and rats have thus far ruled out methionine (an amino acid involved before cysteine in the metabolic process) as the culprit. And we are making continual progress towards an explanation," says Professor Refsum.

Further studies will include experiments on human fat cells, liver cells and stem cells, in addition to more studies on mice and rats. Professor Refsum also wants to further analyse data from studies on Norwegian and international populations.

Levels not diet-related

Findings from other studies indicate that cysteine level is not directly affected by diet.

"We need to investigate this more closely, of course," says Professor Refsum. "Once we determine whether it is possible to alter cysteine levels through diet, we can propose new nutritional recommendations."

Scientists envision the development of medications that regulate cysteine levels in order to prevent obesity and to treat the morbidly obese. Professor Refsum's research group is preparing to test medications that may be able to influence cysteine metabolism in mice.

Their project receives funding under the Research Council's scheme for independent, researcher-initiated basic research projects.

Cysteine

Cysteine is a sulphur-containing amino acid. It is non-essential, which means is it manufactured in the body and does not need to be supplemented through diet. Through a complex biochemical process, non-essential amino acids are formed from nutrients consumed and serve as the building blocks for proteins. The precursor to cysteine is the essential amino acid methionine -- so if intake of methionine is insufficient, cysteine must be supplemented.