Scientists find that a particular enzyme’s location within the fat cell makes all the difference in fat metabolism.
By Christopher Clark
Hormone sensitive lipase (HSL) is a key enzyme that plays a part in the breakdown of stored fat in adipose tissue, allowing it to be used for energy for the body. A team of scientists have found evidence that a deficiency in HSL doesn’t lead to fat buildup, as would be expected, but rather, the opposite.
Adipocytes, the cells that store fat, keep it stored as droplets. The HSL enzyme is found in both the cytosol (the free space inside of the cell) and the nucleus, the “brain” of the cell where DNA is located. It can move in and out of the nucleus to the cytosol via certain processes, and this impacts fat metabolism.
One would think that inhibiting or silencing the expression of this enzyme would lead to uncontrolled fat buildup without the enzyme there to break down fat, yet this isn’t the case. A team of researchers led by Dominique Langin (affiliated with the University of Toulouse in France) investigated HSL at the cell level to understand why. They ascertained that where HSL is localized determines its effect on adipocyte metabolism.
Effects of HSL levels in the nucleus vs. the cytosol
KO group—Lipodystrophy
The researchers found that HSL largely resides in the nuclei of adipocytes, and that the levels there are key for regulating adipose tissue mass. Mice that underwent gene editing to not express HSL (knockout/KO group) showed signs of lipodystrophy, which is the reduction and altered distribution of fat mass. In humans, this condition could mean losing fat in some places but storing more fat in others, while experiencing disruptions in hormones and metabolic functions.
NLS group—Normal fat distribution
The researchers took another group of mice with genes edited to express a form of HSL that contains a certain type of protein sequence called a nuclear localization signal (NLS). This sequence “tags” the HSL to be transported and localized to the nucleus. Normal HSL gets imported to the nucleus with the help of a protein called SMAD3, and the NLS version of HSL gets imported at a higher rate. Because of this, a large portion of HSL ends up inside the nuclei, leaving almost none in the cytosol. Normally, the HSL in the cytosol would be prompted by stress hormones to move to lipid droplets and break down triglycerides, but now, that activity is much lower.
This NLS group did not develop lipodystrophy. Instead, the group actually showed more or less identical levels of overall fat mass and distribution to normal mice. The team suggests based on this that the HSL in the cytosol is not important for maintaining fat mass in adipose tissue, but rather the HSL within the nucleus is.
Hybrid KO–NLS group—Lower fat mass
The research team then crossbred mice from the KO and NLS groups. This produces offspring where the offsprings’ HSL is not fully knocked out (there’s still some expressed) and said HSL has the NLS to boost import to the nucleus. These hybrid offspring had lower levels of HSL expression in the nuclei, in comparison to normal (wild-type/WT) and pure NLS mice. This group showed lower fat mass in their adipose tissue overall, but not to the point of lipodystrophy or metabolic issues, as seen in the pure KO group. While this wasn’t shown to impact their health, the scientists did mention that the data suggests that maintaining enough fat mass in the adipocytes depends heavily on the amount of HSL within the nucleus.
HSL and high-fat diets
Next, the scientists wanted to see if nuclear HSL would adequately hold up in a disease-like situation (obesity in this case, it seems). They tested this by feeding the gene-edited groups plus the WT group a high-fat diet for 3 months.
The NLS and WT groups had almost no difference in fat mass, liver weight, or plasma glucose and insulin levels. This doesn’t mean that the high-fat diet was healthy, but rather further suggests the importance of HSL in the nucleus in regulation of the amount of fat in adipocytes.
The KO group, on the other hand, showed lipodystrophy, enlarged livers, and abnormal glucose and insulin levels. The hybrid KO–NLS mice were not mentioned or had data shown in this specific experiment. Yet, with the patterns in the data, it’s likely that they would have shown mild to moderate lipodystrophy, along with more mild liver, glucose, and insulin issues than the pure KO mice.
The data from these experiments provides evidence to suggest that the amount of HSL in the nucleus plays a key role in helping to maintain the amount and distribution of fat in adipose tissue, the health of the liver, and keeping blood glucose and insulin levels in a normal range (not too high).
HSL and fasting
Through experiments on mice and on isolated human adipocytes, Langin’s team found that HSL interacts with multiple proteins and hormones, facilitating its transfer between nucleus and cytoplasm. They found that during fasting, the export of HSL from the nucleus is notably higher than in a fed state. This leads to more HSL reaching the lipid droplets to break down the triglycerides, lowering overall fat mass in the adipocytes. The reverse was indicated after high-fat feeding: HSL import was high, leading to increased overall fat mass in adipocytes. It should be noted that excess accumulation in adipocyte nuclei was also associated with disruption of glucose balance, which means elevated glucose and insulin levels in the plasma, key signs of insulin resistance.
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More on how HSL impacts fat metabolism
Adipocytes are crucial to energy metabolism, storing fat building blocks as triacylglycerols (or triglycerides) inside of droplets. During fasting, certain hormones trigger a process that prompts both HSL in the cytosol and HSL inside the nucleus (via export) to move to the droplets. Once there, it will then break down those triacylglycerols so that the components can be used for energy.
In addition to nuclear HSL’s role in fat metabolism, it has been implicated that nuclear HSL plays a role in mitochondrial metabolism as well as the expression of genes related to the formation of structures outside and between cells. More research is needed to more clearly understand HSL’s relationship with these genes and nuclear proteins. With this research we will have valuable insights for potential treatments of obesity and other metabolic conditions.
This study was published in the peer-reviewed journal Cell Metabolism.
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Reference
Dufau, J., et al. (2025). Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism. Cell Metabolism, 37(11), P2250–2263.e9. https://doi.org/10.1016/j.cmet.2025.09.014
About the Author
Christopher Clark is enthusiastic about science and fitness, and holds a M.S. in biotechnology. With a background in cellular and molecular biology, he has always enjoyed learning about how living systems work. In his spare time he likes to read, play videogames, and play on his glockenspiel. Currently, he resides in Massachusetts.
