Obesity has become a worldwide epidemic, greatly increasing the incidence of diseases including type 2 diabetes, nonalcoholic fatty liver disease, and other cardiometabolic abnormalities. While lifestyle factors such as diet and exercise play an important role in the development and progression of obesity, scientists have learned that obesity is also associated with intrinsic metabolic abnormalities, including mitochondrial dysfunction. An international team of researchers led by researchers at the University of California, San Diego School of Medicine in mice has now provided a new perspective on how obesity affects mitochondria, the most important energy-producing structure in our cells.
Scientists have found that when mice are fed a high-fat diet, the mitochondria within the animal's fat cells break down into smaller mitochondria, reducing their ability to burn fat. The results of the study also showed that this process is controlled by a single gene, RALA, and that deletion of this gene in mice fed a high-fat diet protects them from excessive weight gain.
Calorie overload from overeating can lead to weight gain and trigger a metabolic cascade that reduces energy burning, making obesity worse," said study leader Alan Saltinge, Ph.D., professor of medicine at the UC San Diego School of Medicine. "The genes we found are key parts of the transition from healthy weight to obesity. Essentially, chronic activation of RALA appears to play a key role in inhibiting energy expenditure in obese adipose tissue. By understanding this mechanism, we are one step closer to developing targeted ** that can address weight gain and associated metabolic dysfunction by increasing fat burning.
Saltiel and colleagues published a paper in Nature Metabolism titled "Obesity leads to mitochondrial fragmentation and dysfunction of white adipocytes due to RALA activation."
Obesity, which affects more than 40% of adults in the United States, occurs when the body accumulates excess fat, which is mostly stored in adipose tissue. Adipose tissue often provides an important mechanical advantage by buffering 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 it is difficult for obese patients to **. How these metabolic abnormalities start is one of the biggest mysteries surrounding obesity.
To answer this question, Saltiel and colleagues took a closer look at the link between obesity and mitochondria in fat cells. "Mitochondrial dysfunction is characteristic of obesity, insulin resistance, and fatty liver disease in humans and rodents," the team wrote. "While mitochondria play an important metabolic role in healthy adipocytes, oxidizing fuels to produce ATP and heat during thermogenesis, mitochondrial function is impaired in obese individuals; However, what drives mitochondrial damage, and how it contributes to obesity and its many complications, remains unknown.
In the study they reported, the team fed mice a high-fat diet and measured the effects of this diet on the mitochondria of animal white adipocytes. They discovered an unusual phenomenon. After eating a high-fat diet, the mitochondria in some of the adipose tissue of the mice were fragmented, forming into many smaller, ineffective mitochondria that burned less fat.
They also found that this metabolic effect is driven by the activity of a single molecule called RALA. "...We found that high-fat diet (HFD) feeding led to mitochondrial fragmentation of groin white adipocytes in male mice, leading to reduced oxidative capacity, a process that relies on the small GTPase RALA," the team continued. "After HFD, RALA expression and activity in white adipocytes increased. ”
RALA has a number of functions, including helping to break down mitochondria when they malfunction. The team's research shows that when this molecule is overactive, it interferes with the normal function of mitochondria, triggering metabolic problems associated with obesity. "Essentially, chronic activation of RALA appears to play a key role in inhibiting energy expenditure in obese adipose tissue," Saltiel said. By understanding this mechanism, we are one step closer to developing targeted ** that can address weight gain and associated metabolic dysfunction by increasing fat burning.
The authors further stated, "Thus, chronic activation of RALA plays a key role in inhibiting energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, leading to weight gain and metabolic dysfunction."
The researchers also showed that by deleting the RALA gene, they were able to protect mice from diet-induced weight gain. "These beneficial effects of RALA deletion are driven by a reversal of increased mitochondrial fission in HFD-induced white adipocytes fed mice," the team explained.
Further studies have shown that some of the proteins affected by RAIA in mice are similar to human proteins associated with obesity and insulin resistance, suggesting that similar mechanisms may be driving obesity in humans.
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