Scientists Discover Enzyme’s Dual Role in Fat Regulation, Opening New Avenues for Obesity Therapy

Enzyme’s Unexpected Dual Function Revealed

Scientists have discovered that a well-known fat-digesting enzyme plays a surprising second role as a genetic regulator within fat cells, according to a new study published in Cell Metabolism. The research reveals that hormone-sensitive lipase (HSL), previously understood only as an enzyme that breaks down stored fat, also enters cell nuclei to control gene activity that maintains healthy fat tissue structure.

Solving a Metabolic Paradox

The finding helps resolve a longstanding paradox in fat cell biology, sources indicate. While HSL’s primary function involves breaking down stored fat for energy release, people with genetic mutations that prevent HSL production don’t become obese but instead develop lipodystrophy—a condition characterized by difficulty maintaining adequate fat levels. This contradiction puzzled researchers for years until the recent discovery of HSL’s nuclear functions., according to market analysis

According to reports, the investigation began when researchers at the University of Toulouse observed HSL protein inside fat cell nuclei. “This [study] was very elegantly done,” says Maria Rohm, a lipid biologist at Helmholtz Munich who was not involved in the research, describing the moonlighting function as “fascinating.”

Experimental Evidence of Nuclear Role

The research team conducted multiple experiments to verify HSL’s nuclear function, the report states. When scientists silenced the HSL gene in cultured human fat cells, they observed increased activity in mitochondrial genes and decreased expression of genes responsible for building fat tissue’s structural framework. The cells also transformed to resemble fat-burning “beige” adipocytes rather than fat-storing white adipocytes.

Further evidence came from genetically modified mouse studies. Analysts suggest that mice engineered to produce HSL with a chemical tag that confined it to the nucleus maintained normal fat stores, while those completely lacking HSL developed lipodystrophy. This indicates that HSL’s tissue maintenance function operates independently of its fat-digesting role in the cytoplasm.

Cellular Shuttling Mechanism Discovered

The research team also traced how HSL moves between cellular compartments under different metabolic conditions, according to their findings. During low-energy states such as fasting, nuclear HSL becomes activated as an enzyme and moves to the cytoplasm to break down fat. When nutrients are abundant, the enzyme hitches a ride on a protein called SMAD3 to return to the nucleus.

This discovery “explains a lot of mystery” in the field, says Erin Kershaw, an endocrinologist at the University of Pittsburgh who was not involved in the study. She suggests that HSL’s direct nuclear regulation might work alongside previously identified indirect mechanisms involving fatty acid signaling.

Implications for Obesity and Metabolic Disease

The researchers found that obese laboratory mice tended to have excess HSL in their fat cell nuclei, suggesting that overactivity of the protein in this location could disrupt fat tissue structure and contribute to obesity development. Although lipodystrophy and obesity appear as opposite conditions, analysts suggest they may represent different manifestations of adipocyte dysfunction related to abnormal nuclear HSL activity.

This could explain why both conditions share certain symptoms, including excess fat accumulation in the liver, according to the research. Dysfunctional fat cells lead to fat buildup in other organs regardless of whether the underlying issue involves deficient or excessive HSL activity.

Potential for New Therapeutic Approaches

The findings could inform future therapies focused on restoring fat cell function rather than simply reducing fat stores, sources indicate. Creating effective drugs requires that scientists “understand the whole biology” of involved proteins, Rohm explains, highlighting the relevance of this type of fundamental research.

This new understanding of HSL’s dual roles may eventually lead to treatments that precisely modulate the enzyme’s activity in specific cellular compartments, potentially offering new strategies for managing obesity, lipodystrophy, and related metabolic disorders.

References

• https://www.cell.com/cell-metabolism/fulltext/S1550-4131(25)00433-4
• https://www.cell.com/cell-metabolism/fulltext/S1550-4131(12)00018-6?_returnUR…
• http://en.wikipedia.org/wiki/Adipocyte
• http://en.wikipedia.org/wiki/Lipodystrophy
• http://en.wikipedia.org/wiki/Cell_nucleus
• http://en.wikipedia.org/wiki/Enzyme
• http://en.wikipedia.org/wiki/Adipose_tissue

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