Fat is in the spotlight again, but the latest news isn’t about how to lose it or why it’s bad for you. Rather, scientists have discovered new insights into how fat cells self-regulate — surprising the researchers themselves — and the findings could lead to new obesity treatments.

The new research in Cell Metabolism involves an enzyme called hormone-sensitive lipase (HSL), long known to enable the release of excess energy from fat cells. After activation by hormones like adrenaline, HSL enters the cytoplasm to break down and release stored fat, which fuels the body during times of fasting.

HSL expression is often tamped down in people with obesity. That seems logical: Dysfunctional HSL allows fat to over-accumulate. But, confoundingly to scientists, people who lack any HSL struggle to maintain enough fat — a condition called lipodystrophy. The new research could begin to help scientists understand why.

For the first time, they’ve identified HSL inside the nuclei of fat cells, where it influences gene expression and helps maintain “perfectly normal fat with all the properties expected for fat cells,” said Dominique Langin, PhD, who led the research and directs the Institute of Metabolic and Cardiovascular Diseases at the University of Toulouse, Toulouse, France.

The research “could explain why during obesity fat tissues stop functioning properly by not being able to store excess calories,” said Dipsikha Biswas, PhD, a researcher at Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark,who was not involved in the research. “This discovery could open up new therapeutic approaches for obesity,” and may shift the focus of interventions “from shrinking fat stores to restoring adipocyte function,” Biswas said.

Langin has been trying to understand HSL for more than two decades. Real progress came in 2014, when US researchers genetically characterized two lipodystrophic people with HSL deficiency. Since then, scientists had suspected the enzyme had capabilities beyond breaking down fat, Langin said. Indeed, his 2019 research found that HSL could engage in protein-protein interaction with ChREBP, a transcription factor involved in turning excess sugar into stored fat. This provided “the first evidence that [HSL] was doing something else than controlling lipolysis,” he said.

The discovery of HSL in the nuclei of fat cells, Langin said, is the most surprising finding about the enzyme in his career.

“You have a protein that had a very conventional, bourgeois activity, and then suddenly you observe it’s a rock star,” he said.

‘You Question Your Results’

Doctoral student and co-author Emeline Récazens first observed the HSL signal on the nucleus. Récazens had been using subcellular imaging to observe interaction between HSL and ChREBP when she noticed the signal. But the idea of nuclear HSL still seemed far-fetched.

“At first we were not even taking this seriously and just making jokes about it, that all we thought of HSL was wrong, which in the end was in part true,” said Jérémy Dufau, PhD, a co-author and postdoctoral researcher in the Department of Cell and Molecular Biology at Karolinksa Institutet, Stockholm, Sweden. “When you start seeing a protein known for this long in a different subcellular compartment, at first you question your results, your protocols, etc. It took a lot of energy to simply prove it was not an artifact, and that HSL was indeed in the nucleus.”

To confirm the presence of nuclear HSL, the team needed to go beyond two-dimensional imaging. First, they used advanced microscopy to reconstruct three-dimensional pictures of the inside of adipocytes. Next, they observed the interaction between a nuclear protein and HSF < 40 nm apart. Finally, they used subcellular fractionation to separate all the components of adipocytes.

At that point, Dufau had been engaged in fruitless attempts to understand why silencing the HSL-encoding gene in human fat cells revved up their mitochondria, making them look more like fat-burning than fat-storing cells.

“Whatever I tried, nothing seemed to explain why we observed such a thing,” Dufau said. “It was only when first seeing data that the nuclear pool of HSL alone was sufficient to influence the biogenesis of mitochondria, that we truly realized the dimension of what we were looking at.”

A Finely Regulated System That Could Unlock Obesity Therapies

Nuclear HSL represents “about 10% of the total HSL pool, so it’s a minor fraction,” Langin said. To understand the significance of nuclear HSL, they observed mice genetically modified to have no HSL at all, or HSL only in the nuclei of fat cells, and compared them to normal mice. Only the “knockout mice” without any HSL had lipodystrophy.

Another key finding concerns HSL’s “continuous shuttling between the cytosol and the nucleus,” Langin said. The researchers identified another protein, SMAD3, that carries HSL from the cytoplasm to the nucleus. The voyage also involves TGF beta signaling — much studied in the context of cancer cells but less understood in adipose tissue. When the body has extra nutrients, it activates TGF beta receptors on the surface of fat cells, prompting SMAD3 to ferry HSL into the nucleus, where it helps ensure storage of excess energy. When the body needs energy, nearly all of the nuclear HSL moves into the cytoplasm, where it resumes its role as an enzyme to break down fat.

They observed that obese mice had excess HSL in the nuclei of fat cells, increased HSL/SMAD3 activity, and problems with glucose regulation and mitochondrial metabolism.

However, the researchers were unable to genetically modify mice to have HSL only in the cytoplasm of fat cells, so they weren’t able to see the effect of having no nuclear HSL.

“The aspect I was intrigued by the most, was the idea that these very well-characterized enzymes and a very well-characterized adipocyte pathway might still be doing something else that we don't fully understand yet,” said Margo Emont, PhD, assistant professor of medicine at Division of Biological Sciences, The University of Chicago, Chicago, who was not involved in the new study.

In both obesity and lipodystrophy, adipose tissue and adipocytes are dysfunctional, Langin said. He hopes to uncover more evidence that nuclear HSL is key to the precise control of adipocyte health.

“What we have to better understand is why the concentration of HSL in the nucleus is so finely tuned,” Langin said. “It seems that too little is deleterious but too much is deleterious as well.”

Further understanding could help improve stratification of people with obesity, he said. For instance, it could be that subgroups have dysregulation of nuclear HSL — which may help determine why some become diabetic or develop heart or kidney failure. Going forward, Langin said, his team will need to confirm in animal models a correlation between different stages of obesity and dysregulated HSL in the nuclei of fat cells. Then, they’ll need to develop a way to modulate nuclear HSL levels to measure the effects on adipose tissue and cardiometabolic complications in animals.

“That would be the proof that in a context of obesity, if you have dysregulation of nuclear HSL, this [helps explain] dysfunctional adipose tissue, [which] leads to cardiovascular and metabolic complications,” Langin said.

The study authors declared no competing or financial conflicts of interest.