Core Insights - The article discusses the metabolic reprogramming that occurs during critical illness, emphasizing the role of inflammation and immune response in altering energy distribution and substrate utilization within the body [6][9][27]. Metabolic Regulation Principles - The priority of substrate utilization shifts during critical illness, with the body first consuming glucose and glycogen, followed by fats and proteins. This shift is crucial for supporting immune and inflammatory cell needs, leading to significant breakdown of muscle and fat tissues [10][13]. - The liver and kidneys enhance gluconeogenesis during critical illness, utilizing lactate, glycerol, and amino acids as substrates, which is vital for maintaining glucose levels [13]. Immune and Inflammatory Cell Metabolism - Immune cells, particularly M1 macrophages and activated T cells, primarily rely on aerobic glycolysis (Warburg effect) for rapid ATP production and biosynthetic precursors, supporting inflammatory responses despite lower energy efficiency [16][18]. - Metabolites such as succinate and itaconate can epigenetically regulate gene expression, influencing inflammation and immune responses [17]. Muscle and Fat Tissue Metabolic Remodeling - In critical illness, white adipose tissue may convert to brown adipose tissue, enhancing thermogenic capacity, while the phenomenon known as the "obesity paradox" suggests that obese individuals may have better survival rates due to greater energy reserves and anti-inflammatory factors [20][22]. - Muscle protein breakdown is significantly increased due to enhanced ubiquitin-proteasome and autophagy mechanisms, leading to muscle wasting [22][26]. Conclusion - The body undergoes metabolic reprogramming during critical illness to enhance immune defense and survival, with a focus on the roles of immune cell metabolism and the breakdown of muscle and fat tissues. Future research should explore innovative interventions targeting metabolic pathways to improve clinical outcomes for critically ill patients [27].