A peripheral lipid sensor GPR120 remotely contributes to suppression of PGD2-microglia-provoked neuroinflammation and neurodegeneration in the mouse hippocampus

Kensuke Iwasa,Nan Yagishita-Kyo,Kota Yamashina,Kei Maruyama,Shinji Yamamoto,Akira Hirasawa,Keisuke Yoshikawa,Yoshinori Takei,Takeo Awaji

doi:10.1186/s12974-021-02361-2

Abstract

BackgroundNeuroinflammation 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 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.MethodsTo reveal the relationship between PGD2-microglia-provoked neuroinflammation and intestinal PUFA/GPR120 signaling, we investigated neuroinflammation and neuronal function with gene and protein expression, histological, and behavioral analysis in GPR120 knockout (KO) mice.ResultsIn the current study, we discovered notable 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 neuroinflammation. GPR120 KO mice exhibited reduced intestinal, plasma, and intracerebral GLP-1 contents. Peripheral administration of a GLP-1 analogue, liraglutide, reduced PGD2-microglia-provoked neuroinflammation and further neurodegeneration in GPR120 KO mice.ConclusionsOur results suggest that neurological phenotypes in GPR120 KO mice are probably caused by dysfunction of intestinal GPR120. These observations raise the possibility that intestinal GLP-1 secretion, stimulated by intestinal GPR120, may remotely contributed to suppress PGD2-microglia-provoked neuroinflammation in the hippocampus.

Highlights

Neuroinflammation is a key pathological component of neurodegenerative disease and is character‐ ized by microglial activation and the secretion of proinflammatory mediators
Numerous FJCpositive neurons were detected in the Wild type (WT) hippocampus after Kainic acid (KA)-induced excitotoxicity, they were hardly detectable in the G-protein-coupled receptor 120 (GPR120) KO hippocampus (Additional file 1: Fig. S1E)
We found an increase in hippocampal PGD2 production in intact GPR120 KO mice without the administration of KA, to a level that was almost comparable to the level observed in the hippocampus of WT mice that received KA (Fig. 2F). PGE2 and P GF2α productions remained unchanged in the GPR120 KO hippocampus (Fig. 2F)

Summary

Introduction

Neuroinflammation is a key pathological component of neurodegenerative disease and is character‐ ized by microglial activation and the secretion of proinflammatory mediators. We previously reported that a surge in prostaglandin D2 (PGD2) production and P GD2-induced microglial activation could provoke neuroinflammation. We reported that a lipid sensor GPR120 (free fatty acid receptor 4), which is expressed in intestine, could be activated by polyunsaturated fatty acids (PUFA), thereby mediating secretion of glucagon-like peptide-1 (GLP-1). Prostaglandins (PGs) are arachidonic acid-derived lipid mediators that exert diverse biological activities through their cognate G-protein-coupled receptors (GPCRs) [1]. We previously reported that a surge in PGD2 production and P GD2-induced microglial activation provoke neuroinflammation and further neurodegeneration in excitotoxic hippocampal lesion [8,9,10]. A surge in P GD2 production and microglial activation are closely connected with neuroinflammation and neurodegeneration in the neurological deficit

Methods

Results

Discussion

Conclusion