Uncovering the mystery of why individuals born with mutations in the gene that encodes HSL—the cytosolic enzyme that releases energy from fat—lose fat instead of gaining it, Dominique Langin, PhD, professor at the University of Toulouse within the I2MC, and colleagues have revealed a surprising new function for the protein. Their study, published in Cell Metabolism and titled “Nuclear Hormone-sensitive Lipase Regulates Adipose Tissue Mass and Adipocyte Metabolism,” shows that HSL not only plays a key role during fat breakdown in adipocytes but also works within the cell nucleus to maintain adipose tissue health.
Our adipocytes, or fat cells, do far more than store excess energy. They manage the body’s fuel economy, accumulating fat in lipid droplets that can later be used when energy is needed, such as between meals. HSL acts as a metabolic switch: when activated by hormones like adrenaline, it breaks down fat to power other organs.
In theory, without HSL, the body should trap fat, leading to obesity. However, mice and humans with HSL gene mutations show the opposite effect. Instead of accumulating fat, they lose it—a condition known as lipodystrophy. Both lipodystrophy and obesity, though seemingly opposite, share a striking commonality: malfunctioning adipocytes that trigger similar metabolic and cardiovascular complications.
To understand this, Langin’s group looked more closely at where HSL operates inside fat cells. “The first surprise was to realize that HSL was not only around the lipid droplet where it should be as an enzyme, but it was also located in the nucleus of the adipocyte,” Langin told GEN. That was the first sign that HSL might be doing something entirely different.
Using advanced imaging, subcellular fractionation, and protein–protein interaction assays, the team confirmed that HSL physically associates with nuclear proteins. This localization, Langin said, hinted at a role in regulating gene expression rather than fat metabolism directly.
To test this, the researchers used CRISPR-Cas9 gene editing to create mice in which altered HSL expression or subcellular localization, redirecting HSL exclusively to the nucleus. Remarkably, these mice had normal fat mass, even though HSL was absent from the cytosol, where fat breakdown typically occurs. In contrast, mice completely lacking HSL developed lipodystrophy. This was an observation that “nuclear HSL is responsible for the maintenance of adipose tissue and having a healthy adipose tissue,” Langin told GEN.
The study shows that nuclear HSL levels must be precisely balanced. Adrenaline, which activates HSL to release fat, also drives its export from the nucleus during fasting. In contrast, “HSL accumulates in the nucleus of adipocytes during high-fat feeding with the converse effect during fasting,” the authors wrote. This imbalance—too little or too much nuclear HSL—may disrupt adipocyte function. “A constant shuttling between the nucleus and the cytosol” seems necessary to keep adipose tissue in balance, Langin told GEN.
Technologically, the work draws on a suite of molecular tools—from CRISPR-Cas9 gene editing to proximity ligation assays and confocal microscopy—to pinpoint HSL’s interactions and movements within the cell. Langin noted that his team is now exploring how HSL’s nuclear role interfaces with chromatin and transcriptional regulation.
Clinically, the implications extend beyond basic biology. At Toulouse University Hospital, Langin also directs molecular genetics studies on metabolic diseases, including monogenic forms of diabetes and lipodystrophy. His group recently diagnosed a nearby patient with HSL deficiency, a rare genetic condition that causes lipodystrophy and related metabolic complications. Understanding these rare defects, he said, could help refine care for patients whose adipose tissue fails to function properly. By understanding the underlying genetics, Langin explained, clinicians can better adjust care and drug treatments for patients with HSL deficiency.
While therapeutic strategies targeting HSL are still distant, the discovery underscores how nuanced adipose biology can be. “HSL has been known since the 1960s as a fat-mobilizing enzyme,” Langin said. “But we now know that it also plays an essential role in the nucleus of adipocytes, where it helps maintain healthy adipose tissue.”
The finding not only resolves a decades-old paradox but also adds a new dimension to how scientists understand obesity, lipodystrophy, and the shared molecular roots of metabolic disease.
