HSL enzyme discovery reveals its role in healthy body fat

Researchers have discovered that an enzyme known for burning fat also supports the maintenance of healthy body fat, challenging its established reputation as merely a switch that releases fuel.

The result clarifies why the loss of this enzyme can reduce fat tissue and cause metabolic problems similar to those associated with obesity.

Fat cells and HSL enzymes

Within mouse and human fat cells, the enzyme was detected not only around stored fat, but also in the areas that regulate genes.

By following this signal, Dominique Langin, Ph.D., of Université de Toulouse in south-western France, found that hormone-sensitive lipase (HSL) performs two separate functions.

This additional function explains why removing the enzyme did not leave fat trapped in cells, as researchers may have anticipated.

Instead, the discovery indicates a more fundamental issue within fat cells, in which storage relies on cellular health rather than the amount of stored fuel alone.

Fat is active

Healthy adipose tissue – the body’s principal fat-storage tissue – holds fuel, releases hormones and contributes to the regulation of blood chemistry. Its primary cells, adipocytes, store excess energy in small droplets within each cell.

Between meals, hormonal signals prompt these droplets to release fatty acids, the small fuel molecules found in fat, for use by the muscles and liver.

Secure fat storage relies on functional fat cells, rather than simply the size of someone’s fat reserves.

HSL not only a fat-burning enzyme

“HSL has been known since the 1960s as a fat-mobilizing enzyme,” said Langin.

That understanding suggested an obvious result: without HSL, fat should accumulate because cells would be unable to release their stores.

However, previous observations in mice and humans found lipodystrophy – insufficient functional fat tissue – when HSL was missing or impaired.

Scientists linked this apparent contradiction to the nucleus, the cellular region responsible for controlling gene activity.

When fat disappears

Lipodystrophy may seem to be obesity’s opposite, since it involves too little fat tissue rather than too much.

Yet in either condition, fat cells may be unable to store and release energy properly, allowing sugar and fatty acids to accumulate in the blood.

When too little functional fat is present, people may develop insulin resistance – an inadequate response to the hormone that removes sugar – followed by blood sugar problems.

This overlapping harm shows why an enzyme associated with fat loss remains relevant to obesity research.

HSL enzymes have another job

The crucial finding emerged when HSL was seen within the nuclei of adipocytes, where changes in gene activity shape cell behaviour.

In the nucleus, HSL interacted with other proteins and helped sustain the programme that maintains fat tissue at a healthy size.

“But we now know that it also plays an essential role in the nucleus of adipocytes, where it helps maintain healthy adipose tissue,” said Langin.

This function recasts the enzyme as more than a single-purpose fat burner, instead making it a regulator of fat-cell identity.

Signals move HSL

Hormonal signals enabled the cell to shift HSL between its different roles.

While fasting, adrenaline helped activate HSL and move it out of the nucleus.

Once outside the nucleus, the enzyme moved back towards fat droplets, helping to release stored fuel for organs.

A high-fat diet in mice altered this distribution, retaining more HSL in the nucleus and indicating that disease may affect its movement.

Genes feel changes

Within the nucleus, the enzyme influenced genes associated with mitochondria – the cellular structures that produce usable energy – and with the framework surrounding fat cells.

When researchers reduced HSL levels in human adipocytes, the mitochondria became more active.

These cells also lowered signals related to the extracellular matrix, the supportive substance around cells as tissue grows.

Together, these effects indicate that nuclear HSL may balance fuel use against the physical maintenance of fat tissue.

Obesity adds pressure

The finding comes as obesity rates already place pressure on clinics, families and budgets. Globally, around 2.5 billion adults had excess weight in 2022, including more than 890 million people living with obesity.

In France, 47.3 percent of adults had excess weight according to Obepi-Roche – a national survey tracking adult weight trends. That is nearly one in every two adults.

These figures make the health of fat cells more than a scientific question, since impaired storage can contribute to diabetes and heart disease over time.

A treatment warning

The finding does not suggest that doctors should simply increase or decrease HSL in fat tissue.

Experiments in mice found that maintaining nuclear HSL preserved fat mass, whereas excess nuclear HSL impaired blood sugar control.

Studies in humans must still determine whether these nuclear patterns occur across different types and stages of obesity.

Any future treatment would need to adjust both the enzyme’s location and its amount with care, rather than merely turning it on or off.

A more careful target

HSL now appears less like a fat-burning instrument and more like a mobile regulator that helps fat cells store, release, repair or use fuel.

This insight allows obesity research to ask more precise questions about cell quality, while treatments must account for the enzyme’s delicate balance within living tissue.