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Aerobic Exercise Regulating Arterial Function by Lactate/GPR81 Signaling Pathway.

Fengzhi Yu1,2, Yilan Guo1, Liang He3

  • 1The Key Laboratory of Adolescent Health Assessment and Exercise Intervention of the Ministry of Education, East China Normal University, Shanghai, People's Republic of China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|September 24, 2025
PubMed
Summary

Aerobic exercise improves arterial function in obese, ovariectomized mice by increasing lactate and activating the GPR81/CREB/eNOS pathway. This highlights a novel mechanism for exercise benefits in cardiovascular health.

Keywords:
GPR81aerobic exercisearterial functionox‐LDL

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Area of Science:

  • Cardiovascular Physiology
  • Endocrinology
  • Metabolic Health

Background:

  • G protein-coupled receptor 81 (GPR81) is a lactate receptor with largely unknown roles in arterial function.
  • Obesity and ovariectomy impair arterial health and are linked to atherosclerosis.
  • Lactate (LA) is the endogenous ligand for GPR81.

Purpose of the Study:

  • To investigate the role of GPR81 in regulating arterial function in a mouse model of impaired arterial health.
  • To elucidate the signaling pathway through which exercise improves arterial function in this model.

Main Methods:

  • A mouse model was created using high-fat diet (HFD) and ovariectomy (OVX) to induce obesity and impaired arterial function.
  • Mice underwent an 8-week aerobic exercise intervention.
  • Gpr81 knockout mice were used to confirm the role of GPR81.
  • Key molecular markers including lactate, GPR81 expression, p-CREB, and eNOS were assessed.

Main Results:

  • OVX and obesity increased arterial stiffness, dyslipidemia, and aortic oxidized low-density lipoprotein (ox-LDL).
  • Aerobic exercise reversed these adverse effects, increasing serum lactate and aortic GPR81 expression.
  • Exercise also increased phosphorylated cAMP-response element-binding protein 1 (p-CREB) and endothelial nitric oxide synthase (eNOS) expression.
  • Exercise failed to improve arterial function in Gpr81 knockout mice.

Conclusions:

  • Exercise enhances arterial function in ovariectomized obese mice, potentially via the lactate/GPR81/p-CREB/CREB/eNOS signaling pathway.
  • GPR81 is crucial for mediating the beneficial effects of exercise on arterial health.
  • This pathway represents a potential therapeutic target for improving cardiovascular function.