A long-standing enigma in the field of fat metabolism has been unraveled by researchers who have identified a nuclear function for hormone-sensitive lipase (HSL). This discovery illustrates how the regulation of HSL within adipocytes links hormonal signaling to the balance of adipose tissue and conditions such as obesity and lipodystrophy. The findings were published in the journal Cell Metabolism by a team led by Dominique Langin, PhD, a professor at the University of Toulouse.
Traditionally, HSL has been recognized as a cytosolic enzyme responsible for releasing energy from stored fat. However, the study reveals that individuals with mutations in the HSL gene lose fat instead of gaining it, resulting in lipodystrophy. This phenomenon suggests that HSL has a crucial role beyond fat breakdown; it also maintains the health of adipose tissue.
Adipocytes, commonly known as fat cells, play a multifaceted role in the body”s energy management. They store excess energy in the form of fat, which can be utilized during periods of energy need, such as between meals. HSL acts as a metabolic switch that, when activated by hormones like adrenaline, initiates the breakdown of fat for energy. The expectation would be that a lack of HSL would lead to fat accumulation and obesity. Surprisingly, both mice and humans with HSL mutations exhibit fat loss instead.
To explore HSL”s role within fat cells, Langin”s team conducted a detailed analysis of its cellular localization. They were taken aback to find that HSL was present not only around lipid droplets, where it functions as an enzyme, but also within the nucleus of adipocytes. This discovery suggested a potential role for HSL in regulating gene expression rather than merely facilitating fat metabolism.
The researchers employed CRISPR-Cas9 gene editing to modify HSL expression in mice, directing HSL exclusively to the nucleus. Remarkably, these genetically altered mice maintained normal fat mass, despite the absence of HSL in the cytosol, where fat mobilization typically occurs. In contrast, mice lacking HSL entirely developed lipodystrophy, reinforcing the idea that nuclear HSL is essential for maintaining healthy adipose tissue.
The study emphasizes the importance of maintaining balanced levels of nuclear HSL. When activated by adrenaline, HSL is exported from the nucleus during fasting periods. Conversely, the protein accumulates in the nucleus during high-fat feeding. This dynamic suggests that an equilibrium of nuclear HSL is critical for proper adipocyte function, and an imbalance may lead to metabolic complications.
Technologically, this research utilized various molecular tools, including proximity ligation assays and confocal microscopy, to investigate HSL”s interactions and movement within cells. Langin mentioned that his team is currently examining how HSL”s nuclear function interacts with chromatin and influences transcriptional regulation.
The clinical implications of this research extend beyond fundamental biology. At the Toulouse University Hospital, Langin also oversees molecular genetics studies focused on metabolic disorders, including monogenic diabetes and lipodystrophy. His team recently identified a patient with a rare HSL deficiency that results in lipodystrophy and related metabolic issues. Understanding these rare genetic conditions can refine treatment strategies for patients with dysfunctional adipose tissue.
While effective therapeutic strategies targeting HSL remain in the future, this discovery highlights the complexity of adipose biology. Langin stated, “HSL has been known since the 1960s as a fat-mobilizing enzyme. But we now know that it also plays an essential role in the nucleus of adipocytes, where it helps maintain healthy adipose tissue.” This finding not only resolves a long-standing paradox in fat metabolism but also enriches the understanding of obesity, lipodystrophy, and their shared molecular foundations.
