Creatine kinase B controls futile creatine cycling in thermogenic fat

Janane F. Rahbani, Anna Roesler, Mohammed F. Hussain, Bozena Samborska, Christien B. Dykstra, Linus Tsai, Mark P. Jedrychowski, Laurent Vergnes, Karen Reue, Bruce M. Spiegelman and Lawrence Kazak ()
Additional contact information
Janane F. Rahbani: McGill University
Anna Roesler: McGill University
Mohammed F. Hussain: McGill University
Bozena Samborska: McGill University
Christien B. Dykstra: McGill University
Linus Tsai: Harvard Medical School
Mark P. Jedrychowski: Harvard Medical School
Laurent Vergnes: David Geffen School of Medicine at UCLA
Karen Reue: David Geffen School of Medicine at UCLA
Bruce M. Spiegelman: Harvard Medical School
Lawrence Kazak: McGill University

Nature, 2021, vol. 590, issue 7846, 480-485

Abstract: Abstract Obesity increases the risk of mortality because of metabolic sequelae such as type 2 diabetes and cardiovascular disease1. Thermogenesis by adipocytes can counteract obesity and metabolic diseases2,3. In thermogenic fat, creatine liberates a molar excess of mitochondrial ADP—purportedly via a phosphorylation cycle4—to drive thermogenic respiration. However, the proteins that control this futile creatine cycle are unknown. Here we show that creatine kinase B (CKB) is indispensable for thermogenesis resulting from the futile creatine cycle, during which it traffics to mitochondria using an internal mitochondrial targeting sequence. CKB is powerfully induced by thermogenic stimuli in both mouse and human adipocytes. Adipocyte-selective inactivation of Ckb in mice diminishes thermogenic capacity, increases predisposition to obesity, and disrupts glucose homeostasis. CKB is therefore a key effector of the futile creatine cycle.

Date: 2021
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DOI: 10.1038/s41586-021-03221-y

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