Thermogenesis by creatine futile cycling: approaching the molecular mechanism – ThermoCreatine

Brown and beige adipocytes can generate heat from chemical energy, independently of canonical thermogenesis processes. These adipocytes feature a creatine-based adaptive thermogenesis process activated not only after short-term cold response and long-term cold acclimation, but also possibly by diet. Spiegelman and collaborators have recently proposed, in 2 articles published in nature in 2021, a mechanism based on the futile cycling of creatine phosphorylation and dephosphorylation in the mitochondrial intermembrane space that explain this adaptative thermogenesis capacity. The authors propose that this creatine futile cycle (CFC) relies on two enzymes that catalyze opposite reactions, leading to the dissipation of chemical energy as heat: the B-type creatine kinase (BCK) transfers energy from ATP to produce phosphocreatine, and the tissue-nonspecific alkaline phosphatase (TNAP) hydrolyses phosphocreatine to liberate creatine, that can cycle back to creatine kinase, and heat.

This topic of adaptative thermogenesis has gained substantial interest over the last 10 years as it opens critical therapeutic strategies to target obesity and metabolic diseases. Before a potential use of such thermogenesis for therapeutic interventions, a detailed molecular and quantitative understanding of the CFC is required. In this project, ThermoCreatine, recognized experts on molecular components and mechanisms of the CFC join their efforts to dissect the molecular details of the enzymatic and heat generation capacity of the CFC using a range of state-of-the-art biophysical, structural and biological methods. By synergizing the highly complementary and interdisciplinary expertise of this research consortium, we expect to to precisely assess the proposed CFC in vivo and in vitro, evaluate its functioning, relevance and impact in comparison to other thermogenesis mechanisms, and facilitate rational drug design and functional studies.