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

Authors

Chunliang Zheng, Xiaohua Li, Shuo Li, Chungen Xing, Chun Cao

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Oct 29, 2026. Epub Oct 29, 2026.

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.

PMID:
42958789
Bibliographic data and abstract were imported from PubMed on 30 Oct 2026.

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