Lactate Drives Pathological Browning of White Adipose Tissue to Aggravate Sepsis-Associated Metabolic Disorders in a GPR81-Dependent Manner.
- 1Department of General Surgery, the Second Affiliated Hospital of Soochow University, Suzhou, China.
- 2Department of Thyroid and Breast Surgery, Suzhou Wuzhong People's Hospital, Suzhou, China.
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.
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BibTeX
@article{zheng2026lactate,
title = {{Lactate Drives Pathological Browning of White Adipose Tissue to Aggravate Sepsis-Associated Metabolic Disorders in a GPR81-Dependent Manner.}},
author = {Chunliang Zheng and Xiaohua Li and Shuo Li and Chungen Xing and Chun Cao},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = oct,
doi = {10.1002/advs.78487},
url = {https://europepmc.org/article/MED/42958789},
note = {CC BY},
}
RIS
TY - JOUR
TI - Lactate Drives Pathological Browning of White Adipose Tissue to Aggravate Sepsis-Associated Metabolic Disorders in a GPR81-Dependent Manner.
AU - Chunliang Zheng
AU - Xiaohua Li
AU - Shuo Li
AU - Chungen Xing
AU - Chun Cao
PY - 2026
DA - 2026/10/29
JO - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO - 10.1002/advs.78487
UR - https://europepmc.org/article/MED/42958789
AB - 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.
SN - 2198-3844
ER -