Lactate Drives Pathological Browning of White Adipose Tissue to Aggravate Sepsis‐Associated Metabolic Disorders in a GPR81‐Dependent Manner

ABSTRACT Lactate serves as a prognostic biomarker for sepsis, yet its adipose‐centered signaling pathway driving persistent metabolic disorders remains unclear. We reveal that lactate accumulation triggers browning of white adipose tissue (WAT) via GPR81 to aggravate sepsis‐induced hypermetabolism, muscle wasting, and insulin resistance. Septic patients exhibit hyperlactatemia and WAT browning, with lactate concentrations correlated with fat and muscle loss. Genetically deleting UCP1 substantially attenuates LPS‐induced hypermetabolism, muscle wasting, and insulin resistance, confirming WAT browning as a major mediator of sepsis‐associated metabolic disorders. Lactate supplementation and pharmacological interventions using glycolysis or lactate dehydrogenase inhibitors identify lactate as the upstream pathogenic trigger. Using siRNA screening, global GPR81 knockout, and AAV9‐mediated adipose‐specific GPR81 knockdown, we identify GPR81 as the lactate receptor mediating UCP1 upregulation. Mechanistically, GPR81 activation induces CTRP6 and p‐p38 to upregulate UCP1. AAV9‐mediated overexpression of CTRP6/MKK6 in GPR81 −/− mice, together with pharmacological downregulation of CTRP6 or inhibition of p‐p38, supports the involvement of this pathway in WAT browning. Taken together, evidence from clinical data, gene‐knockout mice, and primary adipocyte experiments demonstrates that lactate drives WAT browning in a GPR81‐dependent manner to aggravate sepsis‐associated metabolic disorders, identifying potential targets for therapeutic investigation in metabolic disorders unresponsive to conventional anti‐infective and nutritional support treatments.