Abstract
Intensive care unit-acquired weakness (ICU-AW) represents a prevalent and debilitating complication among critically ill patients, distinguished by profound skeletal muscle atrophy and functional deterioration. Leptin, a hormone predominantly released by adipose tissue, has gained recognition for its regulatory roles in appetite control, energy homeostasis, and muscle metabolism. Recent evidence indicates that leptin May contribute to ICU-AW pathogenesis through dual protective and detrimental mechanisms. During physiological conditions, leptin supports muscle preservation by enhancing anabolic signaling while suppressing catabolic processes. The hormone modulates essential pathways, including the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, Forkhead Box O (FOXO) transcription factors, and AMP-activated protein kinase (AMPK), which collectively promote protein synthesis and energy utilization in skeletal muscle. Nevertheless, throughout critical illness, leptin signaling becomes frequently compromised. Increased leptin concentrations may inappropriately stimulate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) and nuclear factor-κB (NF-κB) signalling pathways, initiating the production of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). These cytokines promote muscle wasting through insulin-like growth factor-1 (IGF-1) inhibition, enhanced insulin resistance, and compromised protein synthesis. Furthermore, they stimulate SPRY domain-containing SOCS box protein 1 (SPSB1) expression, which disrupts myocyte fusion and myogenic differentiation. Compounding these consequences, mitochondrial dysfunction, prevalent in critically ill patients, impairs AMPK activity, further hindering muscle regeneration and energy metabolism. In the later stages of critical illness, leptin levels typically decrease, leading to reduced IGF-1 production, disrupted FOXO regulation, and persistent suppression of AMPK signaling. These alterations worsen muscle atrophy and impede recovery. In summary, leptin demonstrates a dual function in ICU-AW, exhibiting both protective and pathological influences based on the illness phase and context. A deeper understanding of its intricate regulatory mechanisms could provide valuable insights into ICU-AW pathogenesis and potential therapeutic strategies.