Creatine-dependent thermogenesis pathway

The creatine-dependent thermogenesis pathway is a metabolic process in beige and brown adipose tissue that generates heat through a futile cycle of creatine phosphorylation and dephosphorylation [3, 5]. Unlike the classical thermogenic pathway mediated by Uncoupling Protein 1 (UCP1), this mechanism relies on mitochondrial creatine kinases (CKMT1/2) to consume ATP and dissipate energy as heat, maintaining thermal homeostasis even in thermoneutral environments [1, 4]. It has emerged as a significant therapeutic target for obesity and type 2 diabetes, as its activation increases whole-body energy expenditure and improves insulin sensitivity [2, 10]. The small molecule SANA (a nitroalkene derivative of salicylate) is a first-in-class activator of this pathway, currently in clinical development, which has shown the ability to reduce body weight and liver fat while preserving lean muscle mass [8, 11]. This pathway offers a complementary approach to appetite-suppressing therapies like GLP-1 agonists by directly boosting the body's metabolic rate [9, 12].

Other names

Creatine-driven substrate cycleFutile creatine cycleCreatine-mediated thermogenesisUCP1-independent thermogenesis

Activation of mitochondrial creatine kinases (CKMT1/2) to stimulate a futile cycle of creatine phosphorylation and dephosphorylation, which consumes ATP and dissipates energy as heat [2, 13].