Scientists have uncovered a hidden role for HSL inside fat cells, linking this enzyme not only to fat breakdown but also to the maintenance of healthy adipose tissue. Credit: Stock
For 60 years, HSL was known for releasing energy from fat, but people born without it lose fat instead of gaining weight—a mystery that Prof. Langin and colleagues have now solved.
After six decades of research on fat metabolism, a new discovery is challenging long-held assumptions about how the body regulates energy. Scientists have found that a key enzyme, long thought to function only in breaking down stored fat, also plays an unexpected role inside the nucleus of fat cells.
Our fat cells, known as adipocytes, do far more than store extra body weight. They serve as vital regulators of the body’…
Scientists have uncovered a hidden role for HSL inside fat cells, linking this enzyme not only to fat breakdown but also to the maintenance of healthy adipose tissue. Credit: Stock
For 60 years, HSL was known for releasing energy from fat, but people born without it lose fat instead of gaining weight—a mystery that Prof. Langin and colleagues have now solved.
After six decades of research on fat metabolism, a new discovery is challenging long-held assumptions about how the body regulates energy. Scientists have found that a key enzyme, long thought to function only in breaking down stored fat, also plays an unexpected role inside the nucleus of fat cells.
Our fat cells, known as adipocytes, do far more than store extra body weight. They serve as vital regulators of the body’s energy supply. These cells store fat in small structures called lipid droplets, which act as reserves that the body can draw upon when energy is needed (for instance, during periods of fasting between meals).
To access these reserves, the body relies on a protein called HSL, which functions like an energy control switch. When energy levels drop, hormones such as adrenaline activate HSL, prompting it to release stored fat to fuel different organs.
Without HSL, it might seem logical that fat would simply build up because the body could no longer access its stored energy. Surprisingly, research involving mice and humans with mutations in the HSL gene reveals the opposite effect. Rather than leading to obesity, the loss of this protein causes a decrease in fat tissue, resulting in a condition called lipodystrophy.
Although obesity and lipodystrophy appear to be opposing conditions, they share an important similarity: in both, adipocytes fail to function properly. This dysfunction disrupts normal metabolism and contributes to similar metabolic and cardiovascular health problems.
A Surprising Discovery Inside Fat Cells
To understand this peculiarity, the research team led by Dominique Langin, professor at the University of Toulouse within the I2MC, noticed that HSL was located in an unexpected area. In adipocytes, the protein is known to be on the surface of lipid droplets, where it acts as an enzyme breaking down fat. But the study reveals that it is also present in the nucleus of fat cells.
HSL contributes to the mobilization of fats stored in the lipid droplet. In the nucleus, HSL ensures the proper functioning of the adipocyte. Credit: I2MC, 2025. Created in https://BioRender.com
“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 defended his doctoral thesis on this subject.
The Fine Regulation of HSL
Moreover, the study shows that the amount of HSL in the nucleus is finely regulated. Adrenaline, which activates the enzyme on the lipid droplet, also promotes its exit from the nucleus. This is what happens during fasting. In a pathological context, the amount of nuclear HSL is increased in obese mice.
“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,” concludes Dominique Langin. This new role explains the lipodystrophy observed in patients lacking HSL and opens avenues for a better understanding of metabolic diseases such as obesity and its complications.
This discovery comes at a timely moment. Overweight and obesity affect one in two adults in France. Worldwide, two and a half billion people are affected. Obesity increases the risk of many diseases, including diabetes and heart disease, and impairs quality of life. Continued research is essential to improve prevention and patient care.
Reference: “Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism” by Jérémy Dufau, Emeline Recazens, Laura Bottin, Camille Bergoglio, Aline Mairal, Karima Chaoui, Marie-Adeline Marques, Veronica Jimenez, Miquel García, Tongtong Wang, Henrik Laurell, Jason S. Iacovoni, Remy Flores-Flores, Pierre-Damien Denechaud, Khalil Acheikh Ibn Oumar, Ez-Zoubir Amri, Catherine Postic, Jean-Paul Concordet, Pierre Gourdy, Niklas Mejhert, Mikael Rydén, Odile Burlet-Schiltz, Fatima Bosch, Christian Wolfrum, Etienne Mouisel, Genevieve Tavernier and Dominique Langin, 23 October 2025, Cell Metabolism. DOI: 10.1016/j.cmet.2025.09.014
Funding: European Foundation for the Study of Diabetes 407 (EFSD/Novo Nordisk Programme for Diabetes Research in Europe 2019 to D.L.), Agence Nationale de la Recherche (ANR-17- 409 CE14-0015Hepadialogue to C.P. and D.L.; ANR-23-IAHU-0011 IHU Health Age to D.L.), European Research Council (ERC) 411 under the European Union’s Horizon 2020 research and innovation programme (SPHERES, ERC)
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