Creatine kinase B controls futile creatine cycling in thermogenic fat

Obesity increases the risk of mortality because of metabolic sequelae such as type 2 diabetes and cardiovascular disease(1). Thermogenesis by adipocytes can counteract obesity and metabolic diseases(2,3). In thermogenic fat, creatine liberates a molar excess of mitochondrial ADP-purportedly via a phosphorylation cycle(4)-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. Upon induction by thermogenic stimuli, creatine kinase B traffics to mitochondria to trigger the futile creatine cycle in thermogenic fat.

Automated summary

The research highlights the impact of obesity on mortality risk due to metabolic sequelae and the role of thermogenesis by adipocytes in combating obesity and metabolic diseases. It identifies creatine kinase B (CKB) as a key player in the futile creatine cycle, crucial for thermogenesis in adipose tissues, and its induction by thermogenic stimuli. The study in mice shows that adipocyte-selective inactivation of CKB reduces thermogenic capacity, increases susceptibility to obesity, and disrupts glucose homeostasis.