(513.2) Role of Mitochondrial TNAP in Thermogenesis and Obesity

Poster Board Number: A373

Yizhi Sun (Dana-Farber Cancer Institute, Harvard Medical School), Bruce Spiegelman (Dana-Farber Cancer Institute, Harvard Medical School)

Adaptive thermogenesis has attracted much attention because of its ability to increase systemic energy expenditure and to counter obesity and diabetes. Thermogenic fat cells use creatine to stimulate futile substrate cycling, dissipating chemical energy as heat; but the molecular basis is unclear. Latest data show that thermogenic fat cells localize tissue-nonspecific alkaline phosphatase (TNAP) to mitochondria to hydrolyze phosphocreatine, which initiates a futile cycle of creatine dephosphorylation and phosphorylation. TNAP expression is powerfully induced when mice are exposed to cold conditions, and its inhibition in isolated mitochondria leads to a loss of futile creatine cycling. In addition, genetic ablation of TNAP in adipocytes reduces whole-body energy expenditure and leads to rapid-onset obesity in mice. These data illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycle. Lastly, TNAP is imported into mitochondria through an untypical pathway and finding the regulators of this process may provide important implications of the controlling of the futile creatine cycling in thermic events.

Support or Funding Information

This work is supported by the American Heart Association postdoctoral fellowship to Y.S., and JPB Foundation 6293803 and NIH grant DK123228 to B.M.S.