Molecular mechanisms of UCP1-independent thermogenesis: the role of futile cycles in energy dissipation.

Adipose tissue thermogenesis has emerged as a prominent research focus for the treatment of metabolic diseases, particularly through mitochondrial uncoupling, which oxidizes nutrients to produce heat rather than synthesizing ATP. Uncoupling protein 1 (UCP1) has garnered significant attention as a core protein mediating non-shivering thermogenesis(NST). However, recent studies indicate that energy dissipation can also occur via UCP1-independent thermogenesis, partially driven by futile metabolic cycles. These cycles involve ATP depletion coupled with reversible energy reactions, resulting in futile energy expenditure. Unlike classical UCP1-mediated thermogenesis, futile cycling is not confined to brown and beige adipose tissue, suggesting a broader range of therapeutic targets. These findings open new avenues for targeting these pathways to enhance metabolic health. This review explores the characteristics and distinctions of the primary metabolic organs (adipose tissue, liver, and skeletal muscle) involved in the futile cycles of thermogenesis. It further elaborates on the cellular and molecular mechanisms underlying calcium, creatine, and lipid cycling, emphasizing their strengths, limitations, and roles beyond thermogenesis.