2. Academic Validation
  3. Glycerol-driven TNAP activation in thermogenesis and mineralization

Glycerol-driven TNAP activation in thermogenesis and mineralization

  • Nature. 2026 Jun;654(8117):198-208. doi: 10.1038/s41586-026-10396-9.
Mohammed Faiz Hussain # 1 2,  Shreya S Krishnan # 2 3,  Brittany L Carroll # 2 3,  Bozena Samborska 1,  Aisha Mousa 4 5,  Alice Williamson 6 7 8,  Maria Delgado-Martin 1 2,  Bindu Y Srinivasu 7,  Jakub Bunk 1 2,  Janane F Rahbani 1 9,  Abel Oppong 1 2,  Anna Roesler 1 2,  Zafir Kaiser 1 2,  Mina Ersin 1 2,  Qiaoqiao Zhang 1 2,  Maria Guerra Martinez 1 2,  Abhirup Shaw 1 2,  Jonathan Cheng 2,  Hannah Klemets 2,  Katalin Kocsis Illes 2 3,  Victoria E DeMambro 10,  Clifford J Rosen 10,  José Luis Millán 11,  Thomas E Wales 12,  Claudia Langenberg 6 7 13,  Marc D McKee 3 4 5,  Alba Guarné 2 3,  Lawrence Kazak 14 15
Affiliations

Affiliations

  • 1 Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
  • 2 Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
  • 3 Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada.
  • 4 Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Quebec, Canada.
  • 5 Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
  • 6 Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
  • 7 Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin, Berlin, Germany.
  • 8 Friede Springer Cardiovascular Prevention Center at Charité, Charité University Medicine Berlin, Berlin, Germany.
  • 9 Department of Medicine, University of Chicago, Chicago, IL, USA.
  • 10 Maine Health Institute for Research, Scarborough, ME, USA.
  • 11 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 12 Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.
  • 13 Max Planck Institute for Molecular Genetics Berlin, Berlin, Germany.
  • 14 Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. [email protected].
  • 15 Department of Biochemistry, McGill University, Montreal, Quebec, Canada. [email protected].
  • # Contributed equally.
PMID: 42020733 DOI: 10.1038/s41586-026-10396-9
Abstract

Tissue-nonspecific Alkaline Phosphatase (TNAP) promotes skeletal mineralization by hydrolysing pyrophosphate1 and has been linked to uncoupling protein 1 (UCP1)-independent adipocyte thermogenesis through the futile creatine cycle through phosphocreatine hydrolysis2,3. Despite TNAP's broad physiological roles, endogenous regulators of its activity have not been defined. Furthermore, the activation mechanism of UCP1-independent thermogenesis has remained unresolved. Here we identify glycerol as an allosteric activator of TNAP. Glycerol binds to a surface pocket distal to the active site, which we term the glycerol pocket, to enhance TNAP activity. Using biophysical, structural, bioenergetic and physiological approaches, we show that the glycerol pocket is required for TNAP-driven thermogenesis. Through this mechanism, TNAP activates the futile creatine cycle, acting as a physiological complement to UCP1. The glycerol pocket is likewise required for optimal osteoblast-regulated mineralization. Human missense variants in this site reduce TNAP-dependent mineralization in vitro and are associated with lower Alkaline Phosphatase activity and bone mineral density, providing genetic evidence that its disruption impairs skeletal physiology.

Figures
Products