Scientists' discovery of a molecular "switch" that activates an energy‑burning pathway in mice has the potential to lead to new treatments for bone disease.
The study, published in Nature , sheds new light on brown fat. Unlike white fat, which stores energy, brown fat cells burn calories, producing heat as a byproduct. For years, it was believed this process relied on a single pathway. More recently, researchers discovered a parallel pathway, but how it became activated remained a mystery.
Researchers led by Lawrence Kazak at McGill University's Rosalind and Morris Goodman Cancer Institute have now identified a molecular 'on switch' for this alternative pathway, known as the futile creatine cycle.
When the body is exposed to cold, it breaks down stored fat to produce heat, releasing glycerol in the process. Working closely with McGill structural biologist Alba Guarné, Canada Research Chair in Macromolecular Machines in DNA Damage and Repair, the researchers found that glycerol binds to an enzyme called TNAP, in what they call the glycerol pocket, switching on this 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."
Implications for bone disease and obesity
Brown fat is being studied for its potential role in metabolism and obesity. While the findings of this study may eventually inform such research, the most immediate implications are towards bone health, where the role of TNAP is already well known.
TNAP is critical for building and maintaining strong bones through calcification. Genetic mutations that impair its function can cause hypophosphatasia, a disorder of "soft bones", leading to fractures, pain and skeletal deformities. The condition is rare, but has higher incidence in parts of Canada, including Quebec and Manitoba, due to inherited genetic mutations in select populations.
By testing TNAP mutations in the lab, the researchers found the molecular switch they identified in energy‑burning cells also plays a direct role in the cells coordinating the mineralization process for hardening bone.
The findings build on earlier work by McGill co‑author Marc McKee , who along with co-author José-Luis Millán of the Sanford Burnham Prebys Medical Discovery Institute, helped develop a first-in-class, bone-targeted enzyme replacement therapy for hypophosphatasia patients with the faulty enzyme.
"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.
The researchers have already identified dozens of potential drug candidates for further study.
About the study
" Glycerol-driven TNAP activation in thermogenesis and mineralization ," by Mohammed Faiz Hussain, Lawrence Kazak et al., was published in Nature.
The research involved collaborations with scientists at Queen Mary University of London, Northeastern University, the Sanford Burnham Prebys Medical Discovery Institute and the Maine Health Institute for Research. Funding was provided by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and the Fonds de recherche du Québec – Santé.
