A researcher at Georgia Regents University has found a gene that is chemically altered in obese people. The next step is to find out if changing that gene can help reduce obesity.
Dr. Shaoyoung Su with the Augusta university’s Medical College of Georgia found that the gene LY86 is highly chemically altered in obese people. He believes such alteration can start in the womb.
For example, in the Dutch famine of 1944, babies born to starving mothers had changes in their DNA that made them better able to survive such deprivation. But when food became more plentiful, that put them at increased risk for cardiovascular disease and diabetes.
Su says it is also possible that a high-fat diet and exposure to some chemicals in early childhood could alter that gene.
The genetic epidemiologist discovered the gene is also associated with increased risk for diabetes, heart disease and cancer.
Now, Su is working to understand whether altering LY86 can fight obesity and other diseases.
Removing gene stops obesity in mice
The study’s lead author Professor James McManaman is Chief of the Basic Reproductive Sciences Section and Vice-Chair of Research in Gynaecology and Obstetrics at the University of Colorado Denver, Anschutz Medical Campus. He fielded ScienceOmega.com’s questions on the surprising results of the work and the long road to potentially applying these findings in human medicine.
The gene under investigation was Plin2, which was discovered in the 1990s. Plin2 is responsible for the production of a protein involved in the metabolism and storage of fat, or lipids.
“It has been implicated as a possible regulator of fat storage in organs such as the liver and mammary gland, which prompted us to generate the mice in the first place,” said Professor McManaman.
Not only were the fat cells of the mouse strain developed by Professor McManaman and his colleagues 20 per cent smaller than those of regular mice, they did not exhibit the kind of inflammation normally associated with obesity. Mice without Plin2 were more sensitive to insulin, had lower triglyceride levels, and showed no signs of the fatty liver disease usually commonplace in obese rodents (and humans). As Professor McManaman explained, the team only predicted the outcomes they observed in part.
“We hypothesised that Plin2 loss would lead to altered metabolism, and we knew that altered metabolism might affect fat accumulation,” he told me. “However, we thought that these effects might be limited to specific tissues. We did not anticipate such a widespread response; altering fat accumulation in liver and adipose tissues, preventing obesity-associated adipose inflammation, and decreasing blood lipid levels. Neither did we anticipate the reduction of food intake or increase in activity that was observed in the mice.”
Although the researchers believe the absence of Plin2 may cause fat to be broken down more quickly in the body, the regulation of fat metabolism and the causes of obesity are complex and not well understood. Accordingly, it is not very likely that Plin2 is the sole gene responsible for obesity.
“Genes such as Plin2 often function in conjunction with other genes and metabolic factors to regulate metabolic balance,” Professor McManaman noted. “Metabolic disorders such as obesity may disrupt this balance, shifting metabolism to increased fat storage – which may depend on Plin2.
“If Plin2 is missing, tissues and organs may adapt to alter food intake or fuel usage, which could lead to decreased fat accumulation. However, it is important to emphasise that we know very few details about how Plin2 works or why its loss prevents obesity in mice on high fat diets.”
As Professor McManaman stressed, we understand very little so far about the mechanisms behind these effects. Many questions remain to be answered concerning the physiological processes involved and the exact repercussions for food intake.
“We don’t know how Plin2 affects the metabolic functions of specific tissues, how the functions of individual tissues are integrated during the development of obesity, or how Plin2-related metabolic alterations influence energy intake and usage,” he explained.
The findings hold potentially major implications for tackling obesity in humans, but it is not yet clear whether the disruption of Plin2 action is able reverse existing obesity. It will also be of critical importance to learn more about the role of Plin2 in human physiology, but Professor McManaman and his fellow researchers believe that understanding the role of Plin2 will provide insights into the way that individuals adapt – or fail to adapt – to excess nutrition, for example.
“As I indicated, we don’t know very much about the role of Plin2 in human metabolism and physiology,” he concluded. “However, humans have a Plin2 gene, and the human and mouse genes appear to be very similar to each other. In addition, Plin2 gene appears to be found in the same organs and tissues in mice and humans. Consequently, we believe it likely that the physiological roles of Plin2 will be similar for mice and humans. If so, Plin2 may contribute to obesity in humans related to excessive food consumption.”