Deleting a Key Gene Shields Against Excess Weight Gain
UC San Diego Study reveals key mechanism behind obesity-related metabolic dysfunction.
The number of people with obesity has nearly tripled since 1975, resulting in a worldwide epidemic. While lifestyle factors like diet and exercise play a role in the development and progression of obesity, scientists have come to understand that obesity is also associated with intrinsic metabolic abnormalities. Now, researchers from the University of California San Diego School of Medicine have shed new light on how obesity affects our mitochondria, the all-important energy-producing structures of our cells.
In a study published today (January 29, 2024) in the journal Nature Metabolism, the researchers found that when mice were fed a high-fat diet, mitochondria within their fat cells broke apart into smaller mitochondria with reduced capacity for burning fat. Further, they discovered that this process is controlled by a single gene. By deleting this gene from the mice, they were able to protect them from excess weight gain, even when they ate the same high-fat diet as other mice.
Caloric overload from overeating can lead to weight gain and also triggers a metabolic cascade that reduces energy burning, making obesity even worse, said Alan Saltiel, PhD, professor in the Department of Medicine at UC San Diego School of Medicine. The gene we identified is a critical part of that 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, which is primarily stored in adipose tissue. Adipose tissue normally provides important mechanical benefits by cushioning vital organs and providing insulation. It also has important metabolic functions, such as releasing hormones and other cellular signaling molecules that instruct other tissues to burn or store energy.
In the case of caloric imbalances like obesity, the ability of fat cells to burn energy starts to fail, which is one reason why it can be difficult for people with obesity to lose weight. How these metabolic abnormalities start is among the biggest mysteries surrounding obesity.
To answer this question, the researchers fed mice a high-fat diet and measured the impact of this diet 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, splitting into many smaller, ineffective mitochondria that burned less fat.
In addition to discovering this metabolic effect, they also discovered that it is driven by the activity of single molecule, called RaIA. RaIA has many functions, including helping break down mitochondria when they malfunction. The new research suggests that when this molecule is overactive, it interferes with the normal functioning of mitochondria, triggering the metabolic issues associated with obesity.
In essence, chronic activation of RaIA appears to play a critical role in suppressing energy expenditure in obese adipose tissue, said Saltiel. By understanding this mechanism, we’re one step closer to developing targeted therapies that could address 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 against diet-induced weight gain. Delving deeper into the biochemistry at play, the researchers found that some of the proteins affected by RaIA in mice are analogous to human proteins that are associated with obesity and insulin resistance, suggesting that similar mechanisms may be driving human obesity.
The direct comparison between the fundamental biology we’ve discovered and real clinical outcomes underscores the relevance of the findings to humans and suggests we may be able to help treat or prevent obesity by targeting the RaIA pathway with new therapies, said Saltiel We’re only just beginning to understand the complex metabolism of this disease, but the future possibilities are exciting.
The study conducted by the UC San Diego researchers provides insight into the intricate mechanisms behind obesity-related metabolic dysfunction. By identifying the role of a single gene in the fragmentation of mitochondria and the subsequent reduction in fat-burning capacity, the researchers have opened up new avenues for developing targeted therapies to combat obesity.
Obesity remains a pressing global health concern, with a significant impact on individuals’ quality of life and overall well-being. With the identification of the RaIA pathway as a potential target for intervention, these findings pave the way for future research and the development of innovative treatments to address weight gain and associated metabolic dysfunctions.
The study’s findings also highlight the importance of further investigating the role of mitochondria in obesity-related metabolic disorders and understanding the underlying mechanisms. By unraveling the complexities of this disease, researchers aim to develop a comprehensive understanding of obesity, leading to more effective prevention and treatment strategies.
As the global obesity epidemic continues to escalate, scientific advancements like this hold promise for millions of individuals struggling with weight management. By targeting the RaIA pathway and enhancing fat-burning capacity, researchers may eventually offer individuals with obesity new hope for overcoming the metabolic challenges associated with the condition.
While these findings are preliminary and require further research, they represent a significant step forward in understanding the intricate relationship between obesity, metabolism, and the functioning of mitochondria. By shedding light on the underlying biological mechanisms behind obesity-related metabolic dysfunction, these research findings offer renewed optimism for combating this global health crisis.
