Creatine kinase B controls futile creatine cycling in thermogenic fat

Abstract

Obesity increases mortality risk because of metabolic sequelae such as type 2 diabetes and cardiovascular disease 1 . Thermogenesis by adipocytes can counter obesity and metabolic diseases 2,3 . In thermogenic fat, creatine liberates a molar excess of mitochondrial ADP to drive thermogenic respiration, hypothesized to be caused by a phosphorylation cycle 4 . However, the proteins that control this futile creatine cycle are unknown. Here we show that creatine kinase B (CKB) is indispensable for futile creatine cycling-based thermogenesis by trafficking to mitochondria through the utilization of an internal mitochondrial targeting sequence. CKB abundance is powerfully induced by thermogenic stimuli in both mouse and human adipocytes. Adipocyte-selective inactivation of Ckb in mice diminishes thermogenic capacity, increases the predisposition to obesity, and disrupts glucose homeostasis. Thus, CKB is a key effector of the futile creatine cycle.The obesity epidemic is a major public health concern 1 . Thermogenesis by brown and beige adipocytes can combat obesity and cardiometabolic diseases 2,5-7 . Adipocyteselective creatine depletion impairs thermogenesis and promotes diet-induced obesity 8,9 , recapitulating the higher fat accretion and lower energy expenditure that occurs with *

ASC‐1 transporter‐dependent amino acid uptake is required for the efficient thermogenic response of human adipocytes to adrenergic stimulation

“…In addition, cAMP‐induced upregulation of CKMT2 and CKMT1a/b was also reduced by the ASC‐1 inhibitor. CKMT1a/b and CKMT2, the mitochondrial creatine kinases, phosphorylate creatine generating phosphocreatine [3] to which creatine kinase B (CKB) can also contribute [56]. Three types of amino acids methionine, glycine, and arginine are required for creatine synthesis [57].…”

Creatine Monohydrate Supplementation Increases White Adipose Tissue Mitochondrial Markers in Male and Female Rats in a Depot Specific Manner

“…Gapdh was used as a housekeeping gene and was not different between groups. Relative differences in Slc6a8 were determined using the 2 -∆∆CT method and normalized to the respective control group [ 34 ].…”

Brown Adipose Tissue Heterogeneity, Energy Metabolism, and Beyond

“…Ablation of the creatine synthesis ratelimiting enzyme glycine amidinotransferase in an adipocytespecific manner in mice resulted in reduced BAT creatine concentration and mild cold intolerance (106). Recently, creatine kinase B (CKB), as the only isoenzyme in brown adipocytes, is proven to be indispensable for the futile creatine cycle-related thermogenesis (107). These studies revealed the critical role of creatine cycling as an alternate thermoregulatory mechanism in brown adipocytes.…”