Octanoic Acid-Rich Enteral Nutrition Alleviates Sepsis-Associated Metabolic Disorders by Suppressing White Adipose Tissue Browning in Mice

Sepsis is a life-threatening clinical syndrome accompanied by severe systemic metabolic disorders, and pathological white adipose tissue (WAT) browning is a core driver that exacerbates negative energy balance, skeletal muscle dysfunction and Insulin resistance. Octanoic acid (OA), a C8 medium-chain fatty acid with superior ketogenic capacity, is a promising functional nutrient for sepsis intervention. This study aimed to investigate the protective effects and underlying mechanism of OA-rich enteral nutrition (EN) on sepsis-associated metabolic disorders. C57BL/6 mice were subjected to lipopolysaccharide (LPS) to establish sepsis models and received OA-rich EN with different concentrations; pharmacological activation of GPR81 and genetic activation of CTRP6 and p38 were used to verify the GPR81-CTRP6-p38 pathway. Results revealed that OA-rich EN dose-dependently increased serum β-hydroxybutyrate levels and decreased lactate accumulation in serum and WAT, with markedly better efficacy than conventional EN. OA-rich EN significantly inhibited LPS-induced upregulation of GPR81, CTRP6, phosphorylated p38 and UCP1 in WAT, mitigated WAT atrophy and abnormal browning, thereby alleviating excessive energy expenditure, body weight loss, skeletal muscle dysfunction and Insulin resistance. Mechanistically, activation of GPR81, CTRP6 or p38 to promote WAT browning reversed the protective effects of OA-rich EN, confirming that OA-rich EN alleviated metabolic disorders by suppressing WAT browning via blocking the lactate-GPR81-CTRP6-p38 pathway. In conclusion, OA-rich EN enhanced hepatic ketogenesis to reduce lactate accumulation, thereby inhibiting the GPR81-CTRP6-p38 pathway and suppressing pathological WAT browning, ultimately alleviating sepsis-associated metabolic disorders. These findings provide a novel targeted nutritional strategy and theoretical basis for optimizing clinical nutritional support in septic patients.