Dysfunction of a Peripheral Lipid Sensor Gpr120 Causes Pgd2-microglia-provoked Neuroinflammation

Abstract Background Neuroinflammation is a key pathological component of neurodegenerative disease and is characterized by microglial activation and the secretion of proinflammatory mediators. We previously reported that a surge in prostaglandin D2 (PGD2) production and PGD2-induced microglial activation could provoke neuroinflammation. We also reported that a lipid sensor GPR120 (free fatty acid receptor 4), which is expressed in enteroendocrine cells in the intestine, could be activated by polyunsaturated fatty acids (PUFA), thereby mediating secretion of glucagon-like peptide-1 (GLP-1). Dysfunction of GPR120 results in obesity in both mice and humans. To reveal the relationship between PGD2-microglia-provoked neuroinflammation and intestinal PUFA/GPR120 signaling, we investigated neuroinflammation and neuronal function in GPR120 knockout (KO) mice. Results In the current study, we discovered notable PGD2-microglia-provoked neuroinflammation (increased PGD2 production and microglial activation) and neurodegeneration (declines in neurogenesis, hippocampal volume, and cognitive function) in GPR120 KO mice. We also found that Hematopoietic-prostaglandin D synthase (H-PGDS) was expressed in microglia, microglia were activated by PGD2, H-PGDS expression was upregulated in GPR120 KO hippocampus, and inhibition of PGD2 production attenuated this neuroinflammatory pathway, suggesting that PGD2-microglia-provoked neuroinflammation was constantly occurring in the hippocampus of GPR120 KO mice. GPR120 mRNA was detected in the intestinal tissues, but not in the brain tissue of WT mice. GPR120 KO mice exhibited reduced intestinal, plasma, and intracerebral GLP-1 levels. Peripheral administration of a GLP-1 analogue, liraglutide, reduced PGD2-microglia-provoked neuroinflammation and further neurodegeneration in GPR120 KO mice. Conclusions Our results suggest that PGD2-microglia-provoked neuroinflammation and neurodegeneration observed in GPR120 KO mice are probably caused by defects in intestinal GPR120 function, and not in the CNS. Our results also suggest that GLP-1 secretion, stimulated by intestinal GPR120, may remotely contribute to suppression of PGD2-microglia-provoked neuroinflammation and further neurodegeneration in the hippocampus.