High-Fat Diets Linked to Mitochondrial Fragmentation: A Key Factor in Obesity
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High-Fat Diets Linked to Mitochondrial Fragmentation: A Key Factor in Obesity
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High-Fat Diets Linked to Mitochondrial Fragmentation: A Key Factor in Obesity
Scientists have discovered that a high-fat diet causes the mitochondria of white adipose tissue to fragment, reducing the energy expenditure of fat cells.
It is well known that an imbalance in energy intake and expenditure in the human body is a direct cause of obesity. The question is, why doesn’t the body expend all excess energy?
Recently, a research team led by endocrinologist Alan R. Saltiel from the University of California, San Diego, published a significant research result in the renowned journal “Nature Metabolism,” providing an unexpected answer.
Based on studies with mouse models, they found that consuming a high-fat diet causes the mitochondria of white adipose tissue cells to fragment, severely impairing mitochondrial metabolic function, thus preventing the utilization of energy stored in white fat, ultimately leading to obesity.
No wonder it’s so difficult to lose excess fat; it turns out that when we consume a calorie bomb, the “factories” of energy expenditure in white adipose tissue cells, the mitochondria, are already blown to pieces.
The good news is that after understanding the molecular mechanism behind this, they have found a way to inhibit the fragmentation of mitochondria in white adipose tissue cells. This might help protect the mitochondria of white adipose tissue cells, promote energy metabolism, and prevent obesity while indulging in hearty meals.
Mitochondria are crucial “factories” for metabolism in the human body.
In healthy fat cells, mitochondria play a significant metabolic role by oxidizing energy substrates to produce ATP and heat. Normal mitochondrial function prevents the excessive accumulation of energy substrates and obesity.
However, numerous studies have shown that mitochondrial function is impaired in obese individuals. Yet, little is known about the driving factors behind mitochondrial damage and how it leads to obesity and its various complications.
To address these questions, the Saltiel team isolated mature adipocytes from control mice and mice fed a high-fat diet and conducted RNA sequencing (RNA-seq). The sequencing results showed that in the inguinal white adipose tissue (iWAT) of mice, the gene Rala, which encodes the small GTPase RalA, was upregulated, and the levels of RalA increased. However, there was no change in RalA levels in brown adipose tissue (BAT).
Subsequently, the Saltiel team developed a mouse model with specific deletion of the Rala gene in adipose tissue (RalaAKO) and found that these mice had reduced insulin-stimulated glucose uptake in iWAT and BAT (indeed, they didn’t store much energy). They also found that under normal food conditions (CD), there was no significant difference in body weight between mutant mice and wild-type mice. However, after switching to a high-fat diet, the increase in body weight in mutant mice was significantly less than that in wild-type mice.
To rule out the influence of brown adipose tissue, the Saltiel team also developed a mouse model with specific deletion of the Rala gene in brown adipose tissue (RalaBKO). However, they did not find any effect of Rala gene in brown adipose tissue on the outcome of a high-fat diet. These results indicate that specific knockout of Rala in white adipose tissue (especially iWAT) can protect mice from the effects of obesity.
In subsequent experiments, the Saltiel team explored the reasons for RalA’s regulation of metabolism health in white adipose tissue. They found that specific deletion of Rala in white adipose tissue can systemically regulate lipid metabolism, thereby improving hepatic steatosis and damage in obesity.
The reason is that the energy expenditure and mitochondrial oxidative phosphorylation levels in mice with specific deletion of Rala in adipose tissue increased, specifically enhancing mitochondrial activity and fatty acid oxidation.
Considering previous research findings that browning of white adipose tissue promotes energy expenditure and prevents obesity, the Saltiel team specifically verified whether white adipose tissue lacking Rala underwent browning.
The result was negative.
This indicates that browning or brown adipose transformation is not the only way for fat to produce heat.
The next question is how RalA affects the mitochondria of white adipose tissue.
Electron microscopy imaging results showed that normal mice with the Rala gene, after consuming a high-fat diet, had smaller, spherical mitochondria in inguinal white adipose tissue (iWAT), which is a sign of damaged mitochondrial function and morphology. However, after knocking out the Rala gene, regardless of the diet, the mitochondria were in a more robust elongated or rod-shaped form.
Mechanistically, elevated RalA levels caused by a high-fat diet relieve the inhibitory phosphorylation of mitochondrial fission protein Drp1, enhance Drp1 activity, increase mitochondrial fission, and thereby inhibit the oxidative function of adipose cell mitochondria.
In summary, the Saltiel team’s research found that a high-fat diet leads to an increase in RalA levels in white adipose tissue, promoting mitochondrial fragmentation, weakening mitochondrial function, affecting energy metabolism, and promoting obesity. Knocking out RalA can eliminate the fattening effect of a high-fat diet by protecting mitochondria.
It is worth noting that research teams have already found small molecule inhibitors of RalA. In the near future, drugs that protect mitochondria may emerge to help address metabolic issues in obese patients.
High-Fat Diets Linked to Mitochondrial Fragmentation: A Key Factor in Obesity
References:
[1].Xia W, Veeragandham P, Cao Y, et al. Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation. Nat Metab. Published online January 29, 2024. doi:10.1038/s42255-024-00978-0
[2].Yan C, Liu D, Li L, et al. Discovery and characterization of small molecules that target the GTPase Ral. Nature. 2014;515(7527):443-447. doi:10.1038/nature13713
(source:internet, reference only)
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