New Research Explains Why Some People Struggle to Lose Weight

Scientists say that obesity changes how energy-producing cells called mitochondria function, causing the body to shift how it metabolizes and stores fat.

Losing weight can be difficult, especially if a person is experiencing obesity. For example, some people find that even after following various diets and exercise programs, the weight just won't come off, which can lead to frustration.

While some researchers say that obesity can cause irreversible brain changes that might contribute to weight loss challenges, a new study suggests that difficulty losing weight may have more to do with what's going on at the cellular level after a person begins overeating.


The study, published on January 29 in Nature Metabolism, found that excess fat associated with obesity may cause changes in how mitochondria behave, leading to more weight gain and metabolic dysfunction.

Using mice, the research team looked at how a high-fat diet impacts mitochondrial function. Mitochondria are the energy-producing part of a cell that drives the cell's biochemical reactions.

The scientists found that when they fed the rodents a high-fat diet, changes occurred in the mitochondria in fat cells beneath the skin, known as subcutaneous fat. Specifically, larger mitochondria broke apart into smaller pieces in a process called fission, and these smaller mitochondria did not burn fat as well as the larger versions.

Typically, in a non-obese situation, these mitochondria maintain stability through a cycle of fusion and fission. However, obesity shifts the mitochondria into fission mode, which promotes the storage of fat, thus making it challenging for a person to lose weight.

The researchers also found that the chronic stimulation of RaIA — a molecule activated by insulin — drives this shift toward fission.

In further experiments, the team found that when they removed the gene linked to RaIA, the mice did not gain weight when fed the high-fat diet. The scientists say that while many questions remain, these findings open the door to new avenues of research focusing on the role of mitochondrial stability in metabolism — potentially leading to new obesity treatments.

Previous research has shown that certain molecules can impact mitochondrial fission. For example, a 2021 study found that the compound SH-BC-893 prevented mitochondrial dysfunction in the fat tissue of mice fed a Western diet, which led to weight loss.


In addition, reports suggest that a new small-molecule drug called CPACC might have the ability to modify mitochondrial behavior by restricting the uptake of magnesium. In a recent mouse study, researchers found the drug candidate caused the mice to lose weight despite consuming a high-fat, high-sugar Westernized diet.

However, these and other potential obesity treatments that target mitochondrial function are still under investigation.


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