Study reveals key mechanism behind obesity-related metabolic dysfunction

The number of obese people has almost tripled since 1975, leading to a global epidemic. Although lifestyle factors, such as diet and exercise, play a role in the development and progression of obesity, scientists have understood that obesity is also associated with intrinsic metabolic abnormalities. .

Now, researchers at the University of California San Diego School of Medicine have shed new light on how obesity affects our mitochondria, the most important energy-producing structures in our cells.

In a study published in Natural metabolism, researchers found that when mice were fed a high-fat diet, the mitochondria in their fat cells separated into smaller mitochondria with a reduced ability to burn fat. Furthermore, they discovered that this process is controlled by a single gene. By removing this gene from mice, they were able to protect them from excessive weight gain, even when they were on the same high-fat diet as other mice.

“Calorie overload from excessive eating can lead to weight gain and trigger a metabolic cascade that reduces energy burning, thereby worsening obesity,” said Alan Saltiel, Ph.D., professor in the Department of Medicine. from UC San Diego School of Medicine. “The gene we identified plays a critical role in the transition from healthy weight to obesity.”

Obesity, which affects more than 40% of adults in the United States, occurs when the body accumulates too much fat, primarily stored in adipose tissue. Adipose tissue normally provides significant mechanical benefits by cushioning and insulating vital organs. It also has important metabolic functions, such as releasing hormones and other cell signaling molecules that tell other tissues to burn or store energy.

In calorie imbalances like obesity, the ability of fat cells to burn energy begins to decline, which is part of the reason why it can be difficult for obese people to lose weight. How these metabolic abnormalities begin is one of the biggest mysteries surrounding obesity.

To answer this question, researchers fed mice a high-fat diet and measured the diet’s impact on their fat cells’ mitochondria, structures within cells that help burn fat. They discovered an unusual phenomenon. After consuming a high-fat diet, mitochondria in parts of the mice’s adipose tissue underwent fragmentation, dividing into many smaller, inefficient mitochondria that burned less fat.

In addition to discovering this metabolic effect, they also discovered that it is due to the activity of a single molecule, called RaIA. RaIA has many functions, including helping to break down mitochondria when they malfunction. New research suggests that when this molecule is overactive, it interferes with the normal function of mitochondria, thereby triggering the metabolic problems associated with obesity.

“Essentially, chronic activation of RaIA appears to play a critical role in suppressing energy expenditure in obese adipose tissue,” Saltiel said. “By understanding this mechanism, we are close to developing targeted therapies that could combat weight gain and associated metabolic dysfunctions by increasing fat burning.”

By deleting the gene associated with RaIA, the researchers were able to protect the mice from diet-induced weight gain. Digging deeper into the biochemistry involved, the researchers found that some of the proteins affected by RaIA in mice are analogous to human proteins associated with obesity and insulin resistance, suggesting that similar mechanisms may be at play. the origin of human obesity.

“The direct comparison between the basic biology we discovered and real-world clinical results highlights the relevance of the findings to humans and suggests that we may be able to help treat or prevent obesity by targeting the RaIA pathway with new therapies,” Saltiel said. “We are just beginning to understand the complex metabolism of this disease, but the future possibilities are exciting.”