Scientists Uncover Hidden Molecular Switch That Can Strengthen Bones

The breakthrough centers on glycerol, a molecule released when fat is broken down in the cold, which activates an enzyme called TNAP and triggers an alternative heat-producing pathway that scientists had struggled to explain for years.

Scientists have uncovered a molecular "switch" in mice that turns on a hidden energy-burning system inside brown fat, a discovery that could eventually help researchers develop new treatments for bone disease.

The findings, published in Nature, provide new insight into how brown fat works. Unlike white fat, which stores energy, brown fat burns calories to generate heat. Scientists long believed this heat production depended on a single biological pathway.

In recent years, however, researchers identified a second pathway operating alongside the original one, but they did not know what activated it.

A team led by Lawrence Kazak at McGill University's Rosalind and Morris Goodman Cancer Institute has now identified the molecular trigger for this alternative system, known as the futile creatine cycle.

Scientists Identify Brown Fat "On Switch"

When the body is exposed to cold temperatures, it breaks down stored fat to create heat. That process releases glycerol, a molecule produced during fat metabolism. Working with McGill structural biologist Alba Guarne, Canada Research Chair in Macromolecular Machines in DNA Damage and Repair, the researchers discovered that glycerol binds to an enzyme called TNAP in a region they describe as the glycerol pocket. This interaction activates the alternative heat-producing pathway.

"This is the first time we've identified how an alternative heat-producing pathway is activated, independent of the classic system," said Kazak, Associate Professor in the Department of Biochemistry and the Canada Research Chair in Adipocyte Biology. "That opens the door to understanding how multiple energy-burning systems work together to keep the body warm at the just-right temperature."

Discovery May Advance Bone Disease Research

Brown fat has attracted attention for its possible role in metabolism and obesity research. While the new findings could eventually contribute to those areas, the researchers say the most immediate significance may involve bone health because TNAP already has a well-established role in bone formation.

The TNAP enzyme is essential for calcification, the process that builds and maintains strong bones. Mutations that reduce TNAP activity can cause hypophosphatasia, a rare disorder sometimes called "soft bones." The condition can lead to fractures, chronic pain, and skeletal abnormalities. Certain inherited mutations have made the disorder more common in parts of Canada, including Quebec and Manitoba.

By studying TNAP mutations in laboratory experiments, the scientists discovered that the same molecular switch involved in energy-burning fat cells also directly affects cells responsible for bone mineralization and hardening.

The work builds on earlier research by McGill co-author Marc McKee and co-author Jose-Luis Millan of the Sanford Burnham Prebys Medical Discovery Institute. Their previous efforts helped produce a first-in-class enzyme replacement therapy designed specifically for hypophosphatasia patients with defective TNAP enzymes.

"This finding opens the door to a new kind of treatment, where increasing the activity of the TNAP enzyme through its glycerol pocket by natural or synthetic bioactive compounds could potentially boost the beneficial actions of the enzyme in patients, to help restore deficient bone mineralization to healthy levels," said McKee, Professor in the Faculty of Dental Medicine and Oral Health Sciences and the Faculty of Medicine and Health Sciences, and Canada Research Chair in Biomineralization.

- ANI