New obesity discovery rewrites decades of fat metabolism science

Without HSL, it would be reasonable to expect fat to build up, as though the body had lost access to its energy supply. Surprisingly, this is not what happens. Research involving both mice and patients with mutations in the HSL gene shows that the lack of this protein does not lead to excess fat or obesity. Instead, affected individuals experience a loss of fat mass, a condition known as lipodystrophy.

Although obesity and lipodystrophy appear to be complete opposites, both involve fat cells that do not function properly. As a result, each condition can contribute to metabolic disturbances and cardiovascular problems.

HSL Found in an Unexpected Location Inside Fat Cells

To understand this surprising behavior, a team led by Dominique Langin, professor at the University of Toulouse within the I2MC, took a closer look at where HSL is found inside adipocytes. The protein is well known for its role at the surface of lipid droplets, where it helps break down stored fat. However, the study revealed that HSL also resides inside the nucleus of fat cells. "In the nucleus of adipocytes, HSL is able to associate with many other proteins and take part in a program that maintains an optimal amount of adipose tissue and keeps adipocytes 'healthy'," explains Jérémy Dufau, co-author of the study, who completed his doctoral thesis on this topic.

The researchers also found that nuclear HSL levels are tightly controlled. Adrenaline, which activates the form of HSL located on lipid droplets, also encourages the protein to leave the nucleus. This process occurs naturally during fasting. In contrast, obese mice show elevated levels of HSL within the nucleus, suggesting a shift in this regulatory system.

A Revised Understanding of HSL's Role in Metabolism

"HSL has been known since the 1960s as a fat-mobilizing enzyme. But we now know that it also plays an essential role in the nucleus of adipocytes, where it helps maintain healthy adipose tissue," says Dominique Langin. This additional responsibility helps explain why the absence of HSL results in lipodystrophy, and it offers new insights into metabolic disorders such as obesity and related health complications.

This discovery appears at a critical time. In France, one in two adults is overweight or obese, and globally the number reaches two and a half billion people. Obesity increases the risk of a range of diseases, including diabetes and heart problems, and often reduces overall quality of life. Continued scientific research is crucial to improving prevention efforts and patient care.