Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation Summary Mitochondrial dysfunction is a characteristic feature of obesity in humans and rodents, insulin resistance, and fatty liver disease. Here we show that feeding a high-fat diet (HFD) causes mitochondrial fragmentation in inguinal white adipocytes of male mice, leading to reduced oxidative capacity through a process dependent on the small GTPase RalA. RalA expression and activity increase in white adipocytes after high-fat diet (HFD). Targeted deletion of RalA in white adipocytes prevents mitochondrial fragmentation and decreases HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to increased mitochondrial fragmentation. Expression in adipose tissue of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Therefore, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction. |
Comments
Researchers found that when mice were fed a high-fat diet, the mitochondria within their fat cells broke down and they were less able to burn fat, leading to weight gain. They also found that they could reverse the effect by targeting a single gene, suggesting a new treatment strategy for obesity.
The number of people with obesity has almost tripled since 1975, causing a global epidemic. While lifestyle factors such as 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 at the University of California, San Diego School of Medicine have shed new light on how obesity affects our mitochondria, the most important structures in our energy-producing cells.
In a study published in Nature Metabolism , researchers found that when mice were fed a high-fat diet, the mitochondria within their fat cells divided into smaller mitochondria with reduced ability to burn fat. Furthermore, they discovered that this process is controlled by a single gene. By removing this gene from the mice, they were able to protect them from excessive 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 the School of Medicine. from UC San Diego. "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 stored primarily in adipose tissue. Adipose tissue typically provides important mechanical benefits by cushioning vital organs and providing insulation. It also has important metabolic functions, such as the release of hormones and other cell signaling molecules that instruct other tissues to burn or store energy.
In the case of caloric imbalances such as obesity, the ability of fat cells to burn energy begins to fail, which is one of the reasons why people with obesity can find it difficult 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 impact of this diet on their fat cell 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 a single molecule, called RaIA that has many functions, including helping to break down mitochondria when they are not working properly. New research suggests that when this molecule is overactive, it interferes with the normal functioning of mitochondria, triggering metabolic problems associated with obesity.
"In essence, 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 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 obesity. human.
"The direct comparison between the fundamental biology we have discovered and actual clinical results underscores the relevance of the findings to humans and suggests that we can help treat or prevent obesity by targeting the RaIA pathway with new therapies," Saltiel said. "We are only beginning to understand the complex metabolism of this disease, but the future possibilities are exciting."
Study co-authors: Wenmin Xia, Preethi Veeragandham, Yu Cao Yayun Xu, Torrey Rhyne, Jiaxin Qian, Ying Jones, Chao-Wei Hung, Zichen Wang, Hiroyuki Hakozaki and Johannes Schoneberg of the Texas Health Science Center, Hui Gao and Michael. Ryden at the Karolinska Institute, Christopher Liddle, Ruth Yu, Michael Downes, Ronald Evans, and Jianfeng Huang at the Salk Institute for Biological Studies; from Cornell University.
This study was funded, in part, by the National Institutes of Health (grants P30DK063491, R01DK122804, R01DK124496, R01DK125820, and R01DK128796).
