Creatine kinase B controls futile creatine cycling in thermogenic fat

Nature. 2021 Feb;590(7846):480-485. doi: 10.1038/s41586-021-03221-y. Epub 2021 Feb 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipose Tissue / cytology
  • Adipose Tissue / enzymology
  • Adipose Tissue / metabolism*
  • Animals
  • Creatine / metabolism*
  • Creatine Kinase, BB Form / deficiency
  • Creatine Kinase, BB Form / genetics
  • Creatine Kinase, BB Form / metabolism*
  • Cyclic AMP / metabolism
  • Energy Metabolism / genetics
  • Female
  • Glucose / metabolism
  • Homeostasis
  • Humans
  • Male
  • Mice
  • Mitochondria / metabolism
  • Obesity / enzymology
  • Obesity / genetics
  • Obesity / metabolism
  • Signal Transduction
  • Thermogenesis*


  • Cyclic AMP
  • Creatine Kinase, BB Form
  • Glucose
  • Creatine