Scientists have identified a protein that has an important role in fragmenting mitochondria in connection with obesity. When researchers deleted the gene that codes for this protein, the mitochondria became longer and thereby also expended more energy. Mice lacking the gene that codes for this protein cannot gain weight.
Energy intake, energy expenditure and weight are clearly related. Expending less energy than intake leads to weight gain.
Conversely, energy expenditure exceeding intake leads to weight loss. However, the energy expenditure in fat cells (white adipose tissue) varies considerably. Sometimes the cells expend more energy than other cells, which influences weight.
Now researchers have characterised what exactly determines whether the fat cells expend considerable energy or remain as a belt of fat around the waist.
“We would like to recreate the same energy expenditure in the cells of people with overweight that people with normal weight have. This will make them lose weight, and in this study, we identified the factors that determine whether the cells have high or low energy expenditure,” explains Alan Saltiel, Professor and Director, UCSD/UCLA Diabetes Research Center and Institute for Diabetes and Metabolic Health, University of California, San Diego, United States.
The research has been published in Nature Metabolism.
Deleted specific genes in mice
Alan Saltiel and colleagues perform research on how insulin controls the uptake of glucose in cells. This is a way of storing energy for leaner times, a process that occurs in both muscle and fat cells.
RalA is a protein required in the signalling pathways for insulin to take up glucose in muscle cells, and researchers have suspected it to be important for some time.
To investigate how RalA regulates energy intake and thereby weight, the researchers deleted the gene that codes for RalA in mice and then fed the mice a high-fat and high-sugar diet to investigate how this affected the mice’s metabolism.
“We expected that deleting the gene for RalA would reduce the glucose uptake in the muscles of the mice and that they would therefore develop diabetes because of very high levels of blood glucose,” notes Alan Saltiel.
Mice unable to gain weight
The results surprised the researchers. As expected, the mice in which the researchers did not delete the gene coding for RalA became obese when fed a high-fat and high-sugar diet.
Conversely, the opposite effect occurred in the mice in which the researchers had deleted the gene coding for RalA. They became resistant to obesity.
“This was a surprise and forced us to revisit the role of RalA in glucose uptake into cells,” says Alan Saltiel.
Mitochondria control energy expenditure
In the next part of the study, the researchers examined fat cells from both groups of mice and found that the mice with functional RalA had shorter mitochondria in the fat cells than the mice in which RalA does not function.
Mitochondria are interesting because longer mitochondria are more active and thus expend more energy. When mice (or humans) eat a high-fat and high-sugar diet, the mitochondria become fragmented, which reduces energy expenditure.
“RalA controls the fragmentation of the mitochondria. Without RalA, the mitochondria cannot be fragmented, and mice without the gene coding for RalA therefore could not gain weight because the long mitochondria kept expending a lot of energy,” explains Alan Saltiel.
New treatments for people with overweight?
Alan Saltiel says that the discovery provides greater insight into the entire interaction between energy intake, energy expenditure, obesity, mitochondria and the signalling pathways involved.
In general terms, the more a person eats, the better the fat cells should be at absorbing energy, so that glucose does not accumulate in the blood and lead to the development of type 2 diabetes.
One way to regulate this is by fragmenting the mitochondria, reducing energy expenditure in the fat cells and enabling cells to store energy better.
This makes good evolutionary sense, but food is no longer lacking – at least not in high-income countries.
According to Alan Saltiel, this insight also opens up the possibility for enabling treatments for people with overweight using the mechanism characterised by the researchers.
“If we can use drugs to ensure that the mitochondria do not become fragmented, this will prevent people from developing obesity, because the fat cells expend energy as rapidly as they absorb it. Another possibility is to determine how to make the mitochondria fuse again. Both options require controlling the processes very precisely,” he concludes.
