Molecular switch discovery could lead to new bone disease treatments

Scientists at McGill University have identified a molecular ’switch’ that activates an alternative energy-burning pathway in mice, which could lead to new treatments for bone disease and metabolic disorders.

The findings, provide fresh insight into how brown fat generates heat and burns calories. Unlike white fat, which stores energy, brown fat consumes calories to produce heat, helping the body maintain its temperature in cold conditions.

For years, scientists believed this heat-producing process relied on a single biological pathway. More recently, researchers discovered a second mechanism known as the futile creatine cycle, though the trigger that activated it remained unknown. 

Discovery of a molecular trigger

The research team, led by Lawrence Kazak at McGill University’s Rosalind and Morris Goodman Cancer Institute, has now identified what they describe as the molecular ’on switch’ for this alternative pathway.

When the body is exposed to cold temperatures, stored fat is broken down to create heat, releasing glycerol as a byproduct. Working with structural biologist Alba Guarné, the scientists discovered that glycerol binds to an enzyme known as TNAP in a region they call the ’glycerol pocket’, activating the heat-producing pathway.

When the body is exposed to cold temperatures, stored fat is broken down to create heat, releasing glycerol as a byproduct

“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.”

Researchers believe the discovery could improve understanding of how the body regulates energy use and temperature, while also opening up new opportunities for medical research.

Potential implications for bone health

Although brown fat is widely studied for its potential role in obesity and metabolism, researchers say the most immediate applications of the findings may relate to bone disease.

TNAP plays a vital role in building and maintaining strong bones by supporting calcification. Genetic mutations that affect the enzyme can cause hypophosphatasia, a rare disorder often described as ’soft bones’, which can lead to fractures, pain and skeletal deformities.

By testing TNAP mutations in laboratory conditions, the team found that the same molecular switch involved in energy-burning cells also has a direct role in the mineralisation process that hardens bone.

Whats next? 

The latest study builds on earlier work by McGill co-author Marc McKee and co-author José-Luis Millán of the Sanford Burnham Prebys Medical Discovery Institute, who helped develop a first-in-class bone-targeted enzyme replacement therapy for patients with hypophosphatasia.

“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 mineralisation 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 Biomineralisation.

This finding opens the door to a new kind of treatment

The researchers have already identified dozens of potential drug candidates for further investigation in the future.