A French study published in the journal Cell Metabolism in October 2025 has found that hormone-sensitive lipase, an enzyme first described in 1964, does far more than release stored fat from the body. It also acts inside the nucleus of fat cells to regulate their health, according to researchers led by Professor Dominique Langin.
Langin heads the team at the Institut des Maladies Métaboliques et Cardiovasculaires in Toulouse, France, that carried out the research. The findings challenge decades of understanding about how the enzyme, known as HSL, works and what happens when it is missing.
Since the 1960s, HSL has been considered the main enzyme responsible for mobilising fat stored in adipose tissue. When the body needs energy, hormones such as adrenaline activate the protein, which breaks down triglycerides and releases fatty acids for other organs to use. Scientists long assumed that people born without HSL would accumulate fat and develop obesity.
That assumption did not hold up. Studies conducted in the early 2000s on knockout mice bred without the HSL gene, and on patients carrying the same mutation, found that a lack of HSL causes lipodystrophy rather than obesity. Lipodystrophy is a condition in which fat cells are unable to store fat properly.
Paradoxically, patients with this condition often develop the same metabolic complications seen in obesity, including insulin resistance, type 2 diabetes, fatty liver disease and dyslipidemia. That happens because the fat that should be stored in adipose tissue is instead deposited in other organs, such as the liver and muscles.
Sixty years after HSL was discovered, Langin's team set out to understand why its absence causes fat loss rather than fat gain.
Discovering HSL's hidden role
The new study examined where HSL operates inside cells and overturned its textbook description. Until now, the enzyme was understood only as a cytoplasmic protein that attaches to lipid droplets to break down fat.
The experiments showed a different picture. In addition to releasing fat for the body to use, the enzyme also migrates into the nucleus of fat cells, known as adipocytes. There, it interacts with regulators of gene expression, including components of RNA polymerase II, which determine which genes are switched on and effectively control how the cell functions.
Inside the nucleus, HSL behaves as a dual regulator. On one hand, it reduces mitochondrial activity, limiting how much energy the cell itself burns. On the other, it speeds up the formation of the extracellular matrix, the structural network that supports and maintains healthy adipose tissue.
The researchers also found that this nuclear function does not depend on the enzyme's classic fat-breaking activity. Even versions of HSL unable to break down stored fat still altered gene expression inside the nucleus.
According to the researchers, HSL reaches the nucleus by hitching a ride with a molecule called SMAD3. In models of diet-induced obesity, such as laboratory mice, this transport becomes exaggerated. With too much HSL accumulating in the nucleus, the fat cell stops burning energy and hardens, developing fibrosis.
Implications for obesity treatment
For medicine, the findings suggest that the central problem in obesity is not simply the accumulation of weight. The rise in nuclear HSL helps explain why adipose tissue becomes unhealthy: it develops fibrosis, mitochondrial failure and fat leakage into the liver and muscles, changes linked to insulin resistance and type 2 diabetes.
The discovery also resolves a longstanding medical puzzle. Patients born with a genetic mutation that prevents them from producing HSL do not become obese. Instead, they lose healthy fat through lipodystrophy and go on to develop severe diabetes and heart problems. HSL, the researchers concluded, does not just empty fat stores. It is essential for keeping the cell functioning properly.
In an era dominated by drugs such as Ozempic, which work by reducing appetite and body weight, the discovery from the University of Toulouse points to a different possible direction for future obesity treatments: correcting the movement of HSL into the nucleus to restore the health of fat cells directly, independent of body weight.
According to the latest data from the World Health Organization, about 2.92 billion people worldwide are affected by overweight. Understanding how fat cells become unhealthy, and not only how the body gains weight, could mark the difference between treating symptoms and addressing the underlying cause, the researchers said.
