International Business Department           Liu Bojia           January 31, 2023

  While modern society has enriched the sources of food acquisition for human beings, it has also made some diseases more likely to occur, such as obesity and diabetes, the incidence of which has increased dramatically in recent decades. Compared to 1975, the number of obese people worldwide has increased twofold. In the eyes of ordinary people, obesity is nothing more than the accumulation of fat on the body, the stomach volume is getting bigger and bigger. But scientists are more curious about why obesity occurs when fat can accumulate quickly, even if the back of the mouth is difficult to reduce.

  According to a recent paper published in Nature Metabolism, one of the biggest mysteries of this obesity is actually related to impaired metabolism in adipose tissue. When you consume energy without moderation, the mitochondrial function of fat cells becomes impaired, making it harder for the body to metabolise and burn off energy through ATP metabolism and heat production.

  Of course, this idea isn't the first time it's been suggested. One study had found that white adipose tissue undergoes metabolic changes such as inflammation and hormone insensitivity when it is chronically enlarged, while mitochondria appear damaged, and that this damage is associated with decreased energy expenditure and insulin resistance, which can promote diabetes.

  In the new study, the authors found that mitochondria are not simply damaged, but more frighteningly, they are "fragmented," and this fragmentation worsens as high-fat dietary intake increases, ultimately leading to the creation of many ineffective, small mitochondria, which essentially do not burn fat to produce calories, exacerbating the process of fat accumulation.

  In their experiments, the authors fed some mice a high-fat diet for a long period of time, and after some time they extracted white adipose tissue from the groin of the mice, and analysed it to show that the mitochondria in it were much smaller and heavily fragmented. Furthermore, this abnormal change was so specific that it was driven to occur by just one gene called RalA.

  Normally, the RalA protein in fat cells can be activated by insulin, causing a series of molecular changes that increase glucose uptake, and another role of RalA is to help break down mitochondria when dysfunction is detected, which removes errant mitochondria in time to maintain a healthier metabolism.

  However, when an individual is obese, the RalA gene can be overactivated for a long period of time, leading to excessive mitochondrial division and fragmentation, which causes even those mitochondria that were working properly to lose their function, exacerbating the rate at which the individual becomes obese.

  As the result of a single change in gene activity, this also makes RalA a target for obesity intervention that can be targeted. In a follow-up experiment, the authors tried to construct a special batch of mice with the RalA gene knocked out of their fat cells. These knockout mice had a lower amount of body fat and would weigh less than their peers who were also on a high-fat diet. Upon examination, the researchers found that their white fat cells were also smaller in size, and the knockout mice also had significantly improved glucose tolerance.

  The benefits weren't just limited to the adipose tissue itself, either; loss of RalA also ameliorated fatty liver degeneration caused by a high-fat diet, which is obtained as a result of enhanced mitochondrial energy metabolism. The discovery of this mechanism is also encouraging for the researchers, who believe that it could lead to a new obesity-targeted therapy that would increase energy burning in individuals, reduce fat accumulation, and restore mitochondrial metabolism to what it should be, primarily through the modulation of RalA.