summary: Researchers have made breakthroughs in understanding the effects of obesity on mitochondria, as detailed in a recent study.
They found that a high-fat diet fragmented the mitochondria in mouse fat cells into smaller, less efficient units, and that the process was controlled by a single gene. Deleting this gene protected the mice from gaining weight despite eating the same high-fat diet.
This study provides new insights into metabolic dysfunction in obesity and paves the way for potential targeted therapies.
Important facts:
- This study revealed that a high-fat diet causes mitochondrial fragmentation within fat cells, reducing their ability to burn fat.
- A single gene associated with the RaIA molecule was found to be responsible for this mitochondrial fragmentation and metabolic disruption in obesity.
- By removing this gene, the researchers were able to protect mice from obesity caused by high-fat diets, suggesting it could be a new therapeutic target for treating obesity in humans.
sauce: UCSD
The number of obese people has nearly tripled since 1975, resulting in a global epidemic. Although 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 underlying metabolic abnormalities.
Now, researchers at the University of California, San Diego School of Medicine have shed new light on how obesity affects the most important energy-producing structures in our cells, the mitochondria.
According to a study published on January 29, 2023. natural metabolismResearchers found that when mice were fed a high-fat diet, the mitochondria in their fat cells broke down into smaller mitochondria with reduced fat-burning ability. Furthermore, they discovered that this process is controlled by a single gene. By deleting this gene from mice, they were able to prevent them from gaining excessive weight even when they ate the same high-fat diet as other mice.
“Excess calories from overeating can lead to weight gain and can also trigger metabolic cascades that reduce energy burn, further exacerbating obesity,” said Dr. Alain Saltiel, professor of medicine at the University of California, San Diego. Ta. “The genes we identified are an important part of 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 typically provides important mechanical advantages by cushioning and providing insulation to vital organs. It also has important metabolic functions, such as releasing hormones and other cell signaling molecules that instruct other tissues to burn or store energy.
In cases of caloric imbalance, such as obesity, the ability of fat cells to burn energy begins to decline. This is one reason why obese people have difficulty losing weight. How these metabolic abnormalities occur is one of the biggest mysteries surrounding obesity.
To answer this question, researchers fed mice a high-fat diet and measured the effect of this diet on fat cell mitochondria, structures inside cells that help burn fat. They discovered an unusual phenomenon. Mitochondria in some fat tissues of mice fed a high-fat diet became fragmented, splitting into many smaller, less effective mitochondria that burned less fat.
In addition to discovering this metabolic effect, they also discovered that it was caused by the activity of a single molecule called RaIA. RaIA has many functions, including helping to destroy mitochondria when they become dysfunctional. New research suggests that when this molecule is overactive, it interferes with normal mitochondrial function and causes metabolic problems associated with obesity.
“Essentially, chronic activation of RaIA appears to play an important role in suppressing energy expenditure in obese adipose tissue,” Saltiel said. “Understanding this mechanism brings us one step closer to developing targeted therapies that can address weight gain and associated metabolic dysfunction by promoting 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, researchers discovered that some of the proteins affected by RaIA in mice are similar to human proteins associated with obesity and insulin resistance. This suggests that similar mechanisms may cause obesity in humans.
“Direct comparisons between the basic biology of our discoveries and real-world clinical results highlight the relevance of our findings to humans, and targeting the RaIA pathway with novel treatments can help reduce obesity and obesity.” This suggests that it may be useful in the treatment or prevention of cancer,” said Professor Saltiel.
“While we are only beginning to understand the complex metabolism of this disease, we are excited about future possibilities.”
Co-authors of this study include: Wenmin Xia, Preethi Veeragandham, Yu Cao Yayun Xu, Torrey Rhyne, Jiaxin Qian, Ying Jones, Chao-Wei Hung, Zichen Wang, Hiroyuki Hakozaki, and Johannes Schoeneberg (University of California). University of San Diego), Peng Zhao (University of Texas Health Science Center), Michael Leiden (Karolinska Institutet), Christopher Riddle, Ruth Yu, Michael Downs, Ronald Evans, Zhang Feng Huang (Salk Institute for Biological Studies), Martin Wabich (Ulm University Medical Center), and Shannon Riley (Weill Medical School) of Cornell University.
Funding: This research was funded in part by the National Institutes of Health (grants P30DK063491, R01DK122804, R01DK124496, R01DK125820, and R01DK128796).
About this genetics and obesity research news
author: Miles Martin
sauce: UCSD
contact: Miles Martin – UCSD
image: Image credited to Neuroscience News
Original research: Open access.
“Obesity causes mitochondrial fragmentation and white adipocyte dysfunction through RalA activation” by Alain Saltiel et al. natural metabolism
abstract
Obesity causes mitochondrial fragmentation and white adipocyte dysfunction through RalA activation
Mitochondrial dysfunction is a characteristic feature of obesity, insulin resistance, and fatty liver disease in humans and rodents. Here we show that high-fat diet (HFD) feeding induces mitochondrial fragmentation in inguinal white adipocytes of male mice and reduces their oxidative capacity through a process dependent on the small GTPase RalA.
RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents mitochondrial fragmentation by increasing fatty acid oxidation and reduces HFD-induced weight gain.
Mechanistically, RalA increases adipocyte division by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, further promoting mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1; DNM1Lis positively correlated with obesity and insulin resistance.
Therefore, chronic activation of RalA plays an important role in suppressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission and contributing to weight gain and metabolic dysfunction. Masu.
