Obesity may be linked with slow metabolism for some

BBC News tells us that the “slow metabolism 'obesity excuse' [is] true”. The news site says that a mutation has been found that slows metabolism and causes people to become severely obese by early childhood.

The search for an obesity gene has been described as the 'holy grail' of obesity research.

A potential candidate, the KSR2 gene, has previously been found to be associated with obesity in mice. In this study researchers wanted to see if it was associated with obesity in humans. They compared the genes of severely obese people, who had been obese since they were children, with a control group from the general population. They found that about 2% of people in the severely obese group carried rare variants in the KSR2 gene, compared with 1% in the controls.

The people who carried these mutations had a history of eating more as children, and had lower metabolic rates than would be expected. The researchers’ laboratory experiments suggest that the diabetic drug metformin may counteract some of the effects of the KSR2 variants.

Overall, these results suggest that KSR2 variants could be a contributing cause of severe obesity in some people.

Obesity is a complex issue. Not all people who have these variants are obese, and not all obese people have these variants. The environment and other genes also play a role. 

Where did the story come from?

The study was carried out by researchers from the Wellcome Trust-MRC Institute of Metabolic Science in Cambridge, and other research centres in the UK. It was funded by the Wellcome Trust, the Medical Research Council, NIHR Cambridge Biomedical Research Centre and the European Research Council. The study was published in the peer-reviewed scientific journal Cell, and is open access.

The BBC News and the Mail Online cover the research appropriately. Their headlines are a little excitable, seeing that mutations in the so-called slow metabolism gene are thought to affect only a small number of obese people.

What kind of research was this?

This was a case control study looking at whether a gene called KSR2 is involved in human obesity.

Previous studies have shown that mice genetically engineered to lack this gene are obese and have impaired glucose tolerance (which in humans are risk factors for type 2 diabetes).

The researchers wanted to see whether this gene might also be linked to obesity in humans.

This is a typical example of one of the methods used by scientists to identify the genes that cause specific characteristics or diseases in humans. When they find that modification of a gene in mice causes symptoms similar to those seen in some humans (in this case obesity), they then look at the gene in people with the symptoms to see if they have mutations in this gene.

What did the research involve?

The researchers looked at the KSR2 gene in people with severe obesity (cases) who first became obese before the age of 10, and also in people from the general population (controls). They wanted to see if there were any changes in the KSR2 gene that were more common in the people who were severely obese than in the general population.

The researchers looked at DNA from 2,101 severely obese people of mixed European descent, and 1,536 people from the general population in the UK (which may contain some severely obese individuals, but not as many as the selected severely obese group). They compared the sequence of nucleotides (the building blocks of DNA, represented by the letters A, C, T and G) in the KSR2 gene in all of these people. Once they had their results, they confirmed them in another sample of 238 cases and 1,117 controls.

They also:

• looked at any changes they found in some of the family members of the severely obese people to see if all the people in the family who carried these changes were obese
• compared characteristics, including metabolic rate, of 18 people who were obese and had KSR2 variants, and 26 equally obese people who did not carry any KSR2 variants
• carried out a range of experiments and modelling to look at what effect the identified variants would have on how the gene, and the protein it produced, functioned in the cell
• looked at mice genetically engineered to lack KSR2

What were the basic results?

The researchers found at least one rare change in KSR2 that would affect how the gene’s instructions were read by the cell in 2.1% of the severely obese people (45 people), and only in 1% of the controls (16 people). There were 27 different changes found in 45 individuals in the obese group, and only seven in the 16 individuals in the control group.

These rare changes in KSR2 were significantly more common in cases than controls.

This was also the case when they pooled the first set of cases and controls with a second set (238 cases and 1,117 controls), and when they excluded people who were overweight or obese from the control sample.

Twenty-three of the changes were found only in cases and not in controls, five were found in both cases and controls and three only in controls who were overweight or obese.

When they looked at 44 family members of the severely obese people who carried KSR2 variants they found that 19 of them also carried the variants, and 18 of these people were overweight or obese.

However, some of the relatives were overweight or obese but didn’t carry the variants. This suggests that it wasn’t only the KSR2 variants that were affecting whether people in these families were obese or not.

Adults with KSR2 variants had a history of increased food-seeking behaviour as children, but by the time they were adults this was less prominent. They had significantly lower metabolic rates than predicted based on their age, gender and body composition. Heart rate was lower in obese adults with KSR2 variants than obese adults without these variants. Obese adults with KSR2 variants had higher fasting insulin levels in their blood than those without the variants, as well as impaired glucose tolerance. These characteristics are linked to the development of type 2 diabetes.

Mice genetically engineered to lack KSR2 ate more than normal mice, and even if they were fed exactly the same food they gained more weight than normal mice.

Some of the effects of the variants identified on cells could be counteracted by treating the cells with the antidiabetic drug metformin. Some of the obese adults with KSR2 variants were reported to have shown improvements in their weight in childhood when prescribed metformin for their severe insulin resistance.

How did the researchers interpret the results?

The researchers conclude that they have found that rare variants in the KSR2 gene are linked to early onset obesity in humans. The findings also show that the gene is an important regulator of energy intake and energy expenditure. They say that drugs that can interfere with the effects of KSR2 may offer a new way to treat obesity and type 2 diabetes.

Conclusion

This study has shown a link between rare changes in the KSR2 gene and severe childhood onset obesity. The changes seem to result in people eating more, particularly in childhood, and burning off calories less effectively. The authors say that their findings need to be confirmed in other studies.

These findings suggest that this gene is playing a role in some people’s obesity. However, about 2% of the severely obese people assessed carried changes in this gene, compared with 1% in the general population. Therefore, the KSR2 gene is not responsible for all cases of obesity. In families with individuals carrying these variants, not all people carrying the variants were obese, and not all of those without the variants were normal weight. This suggests that other genes and environmental factors may influence obesity.

Initial experiments with cells in the lab suggested that the diabetic drug metformin could counteract some of the effects of the genetic variants on the cells. Some of the adults carrying these variants were also reported to have lost weight as children when they were put on the drug. However, this could be because they also made lifestyle changes at the same time (changing their diet and exercise) based on their doctor’s advice. The authors of the study correctly note that prospective controlled studies of the effects of metformin in people carrying these genetic variants need to be carried out to measure its effects objectively.

Metformin works by increasing the body’s sensitivity to insulin and helping the body to make better use of the glucose that is taken in through the diet and this can sometimes lead to weight loss.

Metformin is already the first-line drug of choice in people with type 2 diabetes who are overweight, as it is not associated with weight gain.

We can do little about the genes we were born with, but we can change our lifestyles and behaviour. Your genetic make-up may make it harder for you to lose weight or maintain a healthy weight, but it does not make it impossible. If you are concerned about your weight and its effect on your health, try NHS Choices' free 12-week weight-loss guide.