Amazing stuff! Good news!
"The story scientists have long told about how fat cells function contains a puzzling paradox. An enzyme called hormone-sensitive lipase (HSL) is known to chop up fat stored in these cells, called adipocytes, to release energy. But people who can’t make HSL because of a condition called lipodystrophy don’t store excess fat and aren’t obese—in fact, they struggle to maintain adequate fat levels. HSL, it turns out, has an unexpected second role. Rather than operating only as an enzyme in the cytoplasm as was originally thought, it also enters the nucleus of an adipocyte and controls its gene activity to maintain the health and structure of fat tissue.
Researchers found that silencing the gene for HSL in cultured human fat cells turned up the genes that drive cells’ tiny energy generators, called mitochondria; it also dialed down genes responsible for building the protein framework that gives fat tissue its structure. The cells also started to look more like fat-burning “beige” adipocytes rather than fat-storing white adipocytes, indicating they had more mitochondria. In experiments with genetically modified mice, the team confirmed that the ability to maintain normal fat stores depends on levels of nuclear, not cytoplasmic HSL.
They also found that obese lab mice tended to have excess HSL in the nucleus of their fat cells, suggesting the protein’s overactivity there could alter fat tissue structure and contribute to obesity. The findings could inform future therapies that focus on restoring fat cell function instead of just shrinking fat stores."
From the highlights and abstract:
"Highlights
• Hormone-sensitive lipase is localized within the nuclei of adipocytes
• In vivo, nuclear HSL levels regulate adipose tissue mass
• In vitro, nuclear HSL controls mitochondria and extracellular matrix gene expression
• HSL nuclear level is regulated by TGF-β and PKA signaling pathways
Summary
In adipocytes, hormone-sensitive lipase (HSL) plays a key role in hydrolyzing triacylglycerols that are stored in lipid droplets. Contrary to the expected phenotype, HSL-deficient mice and humans exhibit lipodystrophy.
Here, we show that HSL is also present in the adipocyte nucleus. Mouse models with different HSL subcellular localizations reveal that nuclear HSL is essential for the maintenance of adipose tissue.
Gene silencing in human adipocytes shows that HSL, independently of its enzymatic activity, exerts opposing effects on mitochondrial oxidative phosphorylation and the extracellular matrix.
Mechanistically, we found that HSL accumulates in the nucleus by interacting with the transforming growth factor β (TGF-β) signaling mediator, mothers against decapentaplegic homolog 3 (SMAD3).
Conversely, HSL phosphorylation induces nuclear export. In vivo, HSL accumulates in the nucleus of adipocytes during high-fat feeding with the converse effect during fasting.
Together, our data show that as both a cytosolic enzyme and a nuclear factor, HSL plays a pivotal role in adipocyte biology and adipose tissue maintenance."
Fat-chomping enzyme that ‘moonlights’ as gene regulator could point to obesity treatments "Hormone-sensitive lipase works in the nucleus to keep fat cells healthy, new study suggests"
Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism (open access)
Graphical abstract
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