What is the role of GPR81 in regulating lactate signaling in the body? 

GPR81, identified as a lactate receptor, plays a multifaceted role in regulating lactate signaling across various tissues in the body, influencing metabolic processes, immune responses, and even cancer progression. In adipose tissue, GPR81 activation by lactate inhibits lipolysis, suggesting a role in lipid metabolism and obesity management. This is supported by findings that GPR81 deficiency impairs the ketogenic response and exacerbates hepatic lipid accumulation, indicating its critical role in hepatic lipid homeostasis and potential as a target for treating metabolic disorders. Moreover, dietary lactate supplementation, activating GPR81, has been shown to promote adipose browning and enhance thermogenesis, offering insights into obesity management through the lactate-GPR81 signaling axis. Beyond metabolic regulation, GPR81's expression in renal and vascular tissues implicates it in the modulation of blood pressure and renal hemodynamics through mechanisms involving the potent vasoconstrictor ET-1, highlighting lactate as a paracrine regulator of renal blood flow. In the context of cancer, GPR81 facilitates tumor growth by promoting lactate-induced cell proliferation and reprogramming energy metabolism in breast cancer cells, underscoring its pathological role and potential as a therapeutic target. Additionally, GPR81 activation in the tumor microenvironment suppresses immune surveillance by inhibiting antigen presentation, suggesting a mechanism by which tumors evade immune detection. GPR81 also contributes to neuroprotection and developmental brain angiogenesis, where lactate acting through GPR81 accelerates angiogenesis and attenuates hypoxic/ischemic brain injury by restoring compromised microvasculature. Furthermore, its high expression in type II muscle fibers suggests a role in autocrine signaling within muscles, although its effect on CREB signaling during exercise appears limited. Collectively, these findings underscore GPR81's integral role in lactate signaling, influencing a wide range of physiological and pathological processes.

The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment.

GPR81 promotes breast cancer growth through a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment by inhibiting MHCII presentation, impacting cancer immunotherapy potential.

Endothelin-1 Mediates the Systemic and Renal Hemodynamic Effects of GPR81 Activation

GPR81 activation by lactate inhibits lipolysis in adipocytes and regulates renal hemodynamics through endothelin-1 release, suggesting a role in systemic and renal physiology.

Dietary Lactate Supplementation Protects against Obesity by Promoting Adipose Browning in Mice.

GPR81 plays a crucial role in adipose browning by responding to lactate, promoting thermogenesis, and protecting against obesity through the lactate-GPR81 signaling axis in mice.

Neuronal GPR81 regulates developmental brain angiogenesis and promotes brain recovery after a hypoxic ischemic insult

GPR81 regulates brain angiogenesis by responding to lactate, promoting vascular development and aiding in brain recovery after hypoxic ischemic injury in neonates, as per the research findings.

The Crosstalk between GPR81/IGFBP6 Promotes Breast Cancer Progression by Modulating Lactate Metabolism and Oxidative Stress

GPR81 plays a crucial role in promoting breast cancer progression by modulating lactate metabolism and oxidative stress, highlighting its significance in tumor growth and metabolic pathways.

Neuronal GPR81 regulates developmental brain angiogenesis and promotes brain recovery after a hypoxic ischemic insult

GPR81 in neurons regulates brain angiogenesis by responding to lactate, promoting vascular development and aiding in brain recovery post-hypoxic ischemic injury, as per the research findings.

The roles of GRP81 as a metabolic sensor and inflammatory mediator.

GPR81 acts as the endogenous receptor for lactate, playing a crucial role in metabolic processes and inflammatory responses, highlighting its significance as a metabolic sensor and inflammatory mediator.

The lactate sensor GPR81 regulates glycolysis and tumor growth of breast cancer

GPR81 regulates glycolysis and lactate-dependent ATP production in breast cancer cells, impacting cell proliferation, migration, and invasion, suggesting a critical role in energy metabolism and malignancy.

The lactate receptor GPR81 is predominantly expressed in type II human skeletal muscle fibers: potential for lactate autocrine signaling.

GPR81, predominantly expressed in type II muscle fibers, suggests a potential role for lactate as an autocrine signaling molecule in muscle, influencing energy metabolism without regulating CREB signaling during exercise.

The lactate receptor GPR81 mediates hepatic lipid metabolism and the therapeutic effect of metformin on experimental NAFLDs.

GPR81 mediates hepatic lipid metabolism, influences PGC-1α and L-CPT1, and plays a role in the therapeutic effect of metformin on NAFLDs, rather than directly regulating lactate signaling.