Enzyme 'key to weight gain'

Monday March 16 2009

“The pill that will allow you to eat what you want and not put on weight – thanks to the ‘fat controller’”, the Daily Mail has reported. It said that researchers have pinpointed the enzyme that determines whether the fat we eat is used for energy or whether it is stored in the body. The Daily Express also covered the story, and said the discovery could pave the way for new drug treatments for obesity.

The news reports are overly optimistic about how close scientists have come to altering fat metabolism in humans. This laboratory study in mice highlighted an enzyme called MGAT2, which appears to play a key role in how fat is metabolised in mice fed on a high-fat diet. The findings cannot be directly applied to humans, however, and a ‘fat pill’ remains a long way off. Maintaining a healthy weight through a balanced diet and regular exercise remains the most appropriate way to avoid obesity and its associated health problems.

Where did the story come from?

Dr Chi-Liang Eric Yen and colleagues from the Gladstone Institute of Cardiovascular Disease, the University of California, Novartis Institute for Biomedical Research and the University of Wisconsin-Madison carried out this study. The research was funded by the American Heart Association, the US National Institutes of Health, the US National Research Centre for Research Resources, and the J. David Gladstone Institutes. It was published in the peer-reviewed medical journal Nature Medicine .

What kind of scientific study was this?

The researchers say that animals store fat derived from their diet in their white adipose tissue. During lean times, when calorie intake is low, this storage of fat can be beneficial. However, when dietary fat is abundant, this capacity to store fat may contribute to obesity and its associated metabolic disorders.

This laboratory study in mice investigated the role of an enzyme (acyl CoA:monoacylglycerol acyltransferase-2 or MGAT2) in how fat is used and stored in mice. There are different types of MGAT enzymes found throughout the small intestines of animals and humans, and all of them play a role in fat metabolism. MGAT2 is found in high concentrations in the proximal (nearest the stomach) small intestine.

The researchers used mutant mice that were unable to produce the MGAT2 enzyme and whose overall intestinal MGAT activity was reduced. The effects of a high-fat diet (in which calories from fat accounted for 60% of the females’ diet and 45% of the males’) in these mice was compared with the effects in a high-fat diet in normal mice. The researchers also compared insulin concentrations and glucose tolerance after prolonged high-fat feeding, as well as cholesterol levels and presence of fatty liver.

The researchers then explored precisely which mechanisms differed between the non-MGAT2 mice and the normal mice. The absence of MGAT2 did not appear to affect how dietary fat was absorbed. This led the researchers to theorise that differences in weight gain between the two groups of mice might be due to a reduced absorption of dietary fat into their circulation.

What were the results of the study?

On a high-fat diet, mutant mice gained 40% less weight than normal mice and had 50% lower fat mass. They also had lower concentrations of insulin after fasting, and better glucose tolerance. Their fasting concentrations of total and non-HDL (‘bad’) cholesterol were lower, and they were protected from fatty liver disease. The mutant mice did not seem to eat more than the normal mice, but had greater oxygen consumption.

Further investigation revealed that the mutant mice had a higher metabolic rate, or greater heat production, when resting. Experiments confirmed that while overall fat absorption was not affected, there was less fat absorption in the proximal part of the small intestine, and more fat reaching the mid-part of the intestine than in normal mice. This indicated that fat absorption was delayed. The researchers also found that a reduced amount of fat entered circulation in the mutant mice.

What interpretations did the researchers draw from these results?

The researchers conclude that a deficiency of the MGAT2 enzyme reduces fat uptake in the proximal small intestine and delays the entry of fat into circulation. They say that this change in the way fat is absorbed may reduce fat storage, enhance fat oxidation and metabolic inefficiency. MGAT2 is a “key determinant of energy metabolism in response to dietary fat” and according to the researchers “may be relevant to human obesity”. They say that inhibiting MGAT2 in the small intestine might be useful for treating metabolic diseases caused by excessive fat intake.

What does the NHS Knowledge Service make of this study?

This laboratory study sheds further light on the process of fat metabolism. It also appears to have identified, at least in rats, an enzyme that is key to the metabolism of fats. This is early research, and the study has not investigated possible negative effects of an absence of MGAT2, which may only become apparent in the long term.

It is too soon to claim that this study paves the way for a “fat drug” as reported in the Daily Express . It also remains to be seen whether the presence or activity of MGAT2 in humans explains why some people “don’t get flabby” as The Daily Telegraph claims. This was a study in mice, and it is not known whether removing MGAT2 from human metabolism will have the same effects. It also is unclear how this would be achieved given that the enzyme was removed from these mice by way of genetic mutation.

Prevention of diabetes, obesity and heart disease is a complex issue. Our body weight and metabolism are influenced by many factors, one of which is our genetic makeup. The important factors that influence body weight are food intake and levels of physical activity. Achieving and maintaining a healthy weight through a balanced diet and regular exercise remains the most appropriate way to avoid obesity and its associated health problems. A fat pill that makes these approaches redundant is a long way off.

Analysis by Bazian
Edited by NHS Choices