A newly discovered fat-burning “switch” could pave the way for future treatments that strengthen fragile bones.
Scientists have discovered a molecular “switch” in mice that activates a hidden energy-burning system in brown fat, a breakthrough that could eventually lead to new treatments for bone disease.
The research, published in Nature, offers new insight into brown fat, a special type of fat that burns calories to generate heat. Unlike white fat, which mainly stores energy, brown fat helps the body stay warm. Scientists previously believed this heat-generating process depended on just one biological pathway. More recently, they uncovered a second pathway operating alongside it, but what triggered that system remained unknown.
A team led by Lawrence Kazak at McGill University’s Rosalind and Morris Goodman Cancer Institute has now identified the molecular “on switch” that activates this alternative pathway, called the futile creatine cycle.
Brown Fat Discovery Reveals Hidden Heat Pathway
When the body is exposed to cold temperatures, stored fat is broken down to produce heat. During this process, glycerol is released. Collaborating with McGill structural biologist Alba Guarné, Canada Research Chair in Macromolecular Machines in DNA Damage and Repair, the researchers discovered that glycerol attaches to an enzyme known as TNAP in a region they named the glycerol pocket. This interaction switches on the hidden 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.”
Potential Impact on Bone Disease and Obesity
Brown fat has been widely studied because of its possible role in metabolism and obesity. Although the new findings could eventually contribute to those areas of research, scientists say the discovery may have more immediate importance for bone health because TNAP already plays a major role in maintaining strong bones.
TNAP is essential for calcification, the process that hardens and strengthens bone tissue. Mutations that interfere with the enzyme can cause hypophosphatasia, a rare disorder sometimes referred to as “soft bones.” The disease can result in fractures, pain, and skeletal deformities. Certain inherited mutations have made the condition more common in parts of Canada, including Quebec and Manitoba.
Laboratory tests on TNAP mutations revealed that the same molecular switch involved in energy-burning fat cells also directly affects the cells responsible for bone mineralization.
The new findings build on earlier work by McGill co-author Marc McKee and co-author José-Luis Millán of the Sanford Burnham Prebys Medical Discovery Institute. Their previous research helped lead to a first-in-class enzyme replacement therapy designed 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.
Researchers have already identified dozens of possible drug candidates for future testing.
Reference: “Glycerol-driven TNAP activation in thermogenesis and mineralization” by Mohammed Faiz Hussain, Shreya S. Krishnan, Brittany L. Carroll, Bozena Samborska, Aisha Mousa, Alice Williamson, Maria Delgado-Martin, Bindu Y. Srinivasu, Jakub Bunk, Janane F. Rahbani, Abel Oppong, Anna Roesler, Zafir Kaiser, Mina Ersin, Qiaoqiao Zhang, Maria Guerra Martinez, Abhirup Shaw, Jonathan Cheng, Hannah Klemets, Katalin Kocsis Illes, Victoria E. DeMambro, Clifford J. Rosen, José Luis Millán, Thomas E. Wales, Claudia Langenberg, Marc D. McKee, Alba Guarné and Lawrence Kazak, 22 April 2026, Nature.
DOI: 10.1038/s41586-026-10396-9
The project involved scientists from Queen Mary University of London, Northeastern University, the Sanford Burnham Prebys Medical Discovery Institute, and the Maine Health Institute for Research. Funding came from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Fonds de recherche du Québec – Santé.
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