Mechanism of LMNB1 activating GPR84 through JAK-STAT pathway to mediate M2 macrophage polarization in lung cancer.

BACKGROUND: It is reported that G protein-coupled receptor 84 (GPR84) can participate in inflammation and immune regulation to repress anti-tumor responses. However, the function of GPR84 in lung cancer (LC) and its potential molecular mechanisms are still largely unknown. METHODS: Bioinformatics and molecular experiments were employed to assess the expression of GPR84 in LC. The pathways enriched by GPR84 were analyzed by the Kyoto Encyclopedia of Genes and Genomes. Bioinformatics prediction identified the potential upstream regulatory factors of GPR84, which were verified through dual luciferase and chromatin immunoprecipitation experiments. Cell viability was measured by methyl thiazolyl tetrazolium assay. The expression levels of key proteins related to the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway such as JAK2, p-JAK2, p-STAT3, and STAT3 were detected by western blot. Macrophages were co-cultured with LC cells. Flow cytometry was employed to examine the proportion of mannose receptor-positive cells. The expression levels of M2 polarization marker genes chitinase-like protein 3, arginase-1, and found in inflammatory zone 1 were measured by quantitative reverse transcription polymerase chain reaction. We applied an enzyme-linked immunosorbent assay to determine levels of cytokines (interleukin-10 and transforming growth factor beta) to evaluate the M2 macrophage polarization. RESULTS: GPR84 was highly expressed in LC and substantially enriched in the JAK-STAT pathway. GPR84 facilitated the M2 polarization of macrophages in LC. Adding the JAK-STAT pathway inhibitor weakened the promoting effect of GPR84 overexpression on M2 macrophage polarization. Furthermore, GPR84 also had an upstream regulatory factor lamin B1 (LMNB1). Knocking down LMNB1 blocked the JAK-STAT signaling pathway to repress M2 macrophage polarization in LC, while overexpression of GPR84 reversed the impact of LMNB1 knockdown on macrophage polarization. CONCLUSION: The project suggested that the LMNB1/GPR84 axis can facilitate M2 polarization of macrophages in LC by triggering the JAK-STAT pathway. Targeting LMNB1/GPR84 or blocking the JAK-STAT pathway may be a novel approach for LC diagnosis and treatment.

Sodium octanoate mediates GPR84-dependent and independent protection against sepsis-induced myocardial dysfunction.

INTRODUCTION: This study aims to evaluate the therapeutic effects of sodium octanoate (SO), a medium-chain fatty acid salt, on SIMD in a murine model and to explore its underlying mechanisms. METHODS: Male mice were subjected to sepsis models through two methods: intraperitoneal injection of lipopolysaccharide (LPS) and cecal ligation and punction (CLP). Mice received interval doses of SO every 2 hours or 4 hours for a total of six times or three times after LPS treatment. The relationship between SO and G protein-coupled receptor 84 (GPR84) was evaluated through GEO data analysis and molecular docking studies. DBA/2 mice were used to study the role of the GPR84 protein in the SO-mediated protection. Energy metabolomics was utilized to comprehensively assess the impact of SO on the levels of cardiac energy metabolic products in septic mice. histone modification identification techniques were used to further identify the specific sites of histone modification in the hearts of SO-treated septic mice. RESULTS: SO treatment significantly improved myocardial contractile function, restored the oxidative stress imbalance and enhanced the myocardium's resistance to oxidative injury. SO significantly promotes the expression of GPR84. The loss of GPR84 function markedly attenuates the protective effects of SO. SO enhanced myocardial energy metabolism by promoting the synthesis of acetyl-CoA and upregulating genes involved in fatty acid ß-oxidation which were abolished by medium-chain acyl-CoA dehydrogenase (MCAD) knockdown. SO induced histone acetylation, particularly at H3K123 and H3K80. CONCLUSION: Our study demonstrates that SO exerts protective effects against SIMD through both GPR84-mediated anti-inflammatory and antioxidant actions and GPR84-independent enhancement of myocardial energy metabolism, possibly mediated by MCAD.

Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway.

Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product "sperminal" is reduced to "sperminol." Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy in vitro. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones in vitro, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.

G-protein-coupled receptor 84 regulates acute inflammation in normal and diabetic skin wounds.

Lipids have emerged as potent regulators of immune cell function. In the skin, adipocyte lipolysis increases the local pool of free fatty acids and is essential for coordinating early macrophage inflammation following injury. Here, we investigate G-protein-coupled receptor 84 (GPR84), a medium-chain fatty acid (MCFA) receptor, for its potential to propagate pro-inflammatory signaling after skin injury. GPR84 signaling was identified as a key component of regulating myeloid cell numbers and subsequent tissue repair through in vivo administration of a pharmacological antagonist and the MCFA decanoic acid. We found that impaired injury-induced dermal adipocyte lipolysis is a hallmark of diabetes, and lipidomic analysis demonstrated that MCFAs are significantly reduced in diabetic murine wounds. Furthermore, local administration of decanoic acid rescued myeloid cell numbers and tissue repair during diabetic wound healing. Thus, GPR84 is a readily targetable lipid signaling pathway for manipulating injury-induced tissue inflammation with beneficial effects on acute diabetic healing.

Regulation of the pro-inflammatory G protein-coupled receptor GPR84.

GPR84 is an understudied rhodopsin-like class A G protein-coupled receptor, which is arousing particular interest from a therapeutic perspective. Not least this reflects that gpr84 expression is significantly up-regulated following acute inflammatory stimuli and in inflammatory diseases, and that receptor activation plays a role in regulating pro-inflammatory responses and migration of cells of the innate immune system such as neutrophils, monocytes, macrophages and microglia. Although most physiological responses of GPR84 reflect receptor coupling to Gαi/o-proteins, several studies indicate that agonist-activated GPR84 can recruit arrestin adaptor proteins and this regulates receptor internalisation and desensitisation. To date, little is known on the patterns of either basal or ligand regulated GPR84 phosphorylation and how these might control these processes. Here, we consider what is known about the regulation of GPR84 signalling with a focus on how G protein receptor kinase-mediated phosphorylation regulates arrestin protein recruitment and receptor function. LINKED ARTICLES: This article is part of a themed issue GPR84 Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.10/issuetoc.

Function and regulation of GPR84 in human neutrophils.

Human neutrophils are components of the innate immune system and are the most abundant white blood cells in the circulation. They are professional phagocytes and express several G protein-coupled receptors (GPCRs), which are essential for proper neutrophil functions. So far, the two formyl peptide receptors, FPR1 and FPR2, have been the most extensively studied group of neutrophil GPCRs, but recently, a new group, the free fatty acid (FFA) receptors, has attracted growing attention. Neutrophils express two FFA receptors, GPR84 and FFA2, which sense medium- and short-chain fatty acids respectively, and display similar activation profiles. The exact pathophysiological role of GPR84 is not yet fully understood, but it is generally regarded as a pro-inflammatory receptor that mediates neutrophil activation. In this review, we summarize current knowledge of how GPR84 affects human neutrophil functions and discuss the regulatory mechanisms that control these responses, focusing on the similarities and differences in comparison to the two FPRs and FFA2. LINKED ARTICLES: This article is part of a themed issue GPR84 Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.10/issuetoc.

GPR84 in physiology-Many functions in many tissues.

Members of the GPCR superfamily have a wide variety of physiological roles and are therefore valuable targets for developing effective medicines. However, within this superfamily are receptors that are less well characterized and remain orphans, including GPR84. This receptor is stimulated by ligands derived from dietary nutrients, specifically medium chain fatty acids (C9-14), and novel synthetic agonists. There are data demonstrating the role of GPR84 in inflammatory pathways, in addition to emerging data suggesting a key role for GPR84 as a nutrient-sensing GPCR involved in metabolism by sensing energy load via nutrient exposure and subsequent signalling leading to modulation of food intake. Exploring GPR84 pharmacology, its localization and what drives its expression has revealed multiple roles for this receptor. Here, we will reflect on these various roles of GRP84 demonstrated thus far, primarily by exploring data from pre-clinical and clinical studies in various physiological systems, with a specific focus on the gastrointestinal tract. LINKED ARTICLES: This article is part of a themed issue GPR84 Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.10/issuetoc.

Transcriptional profiling of zebrafish identifies host factors controlling susceptibility to Shigella flexneri.

Shigella flexneri is a human-adapted pathovar of Escherichia coli that can invade the intestinal epithelium, causing inflammation and bacillary dysentery. Although an important human pathogen, the host response to S. flexneri has not been fully described. Zebrafish larvae represent a valuable model for studying human infections in vivo. Here, we use a Shigella-zebrafish infection model to generate mRNA expression profiles of host response to Shigella infection at the whole-animal level. Immune response-related processes dominate the signature of early Shigella infection (6 h post-infection). Consistent with its clearance from the host, the signature of late Shigella infection (24 h post-infection) is significantly changed, and only a small set of immune-related genes remain differentially expressed, including acod1 and gpr84. Using mutant lines generated by ENU, CRISPR mutagenesis and F0 crispants, we show that acod1- and gpr84-deficient larvae are more susceptible to Shigella infection. Together, these results highlight the power of zebrafish to model infection by bacterial pathogens and reveal the mRNA expression of the early (acutely infected) and late (clearing) host response to Shigella infection.

Structural and pharmacological characterization of a medium-chain fatty acid receptor GPR84 in common carp (Cyprinus carpio).

The medium-chain fatty acid receptor GPR84, a member of the G protein-coupled receptor family, is mainly expressed in macrophages and microglia, and is involved in the regulation of inflammatory responses and retinal development in mammals and amphibians. However, structure, tissue distribution, and pharmacology of this receptor have rarely been reported in fish. In this study, we cloned the coding sequence (CDS) of common carp GPR84 (ccGPR84), examined its tissue distribution, and explored its cellular signaling function. The results showed that the CDS of ccGPR84 is 1191 bp and encodes a putative protein with 396 amino acids. Phylogenetic and chromosomal synteny analyses revealed that ccGPR84 was evolutionarily conserved with Cyprinids. Real-time quantitative PCR (qPCR) indicated that ccGPR84 was predominantly expressed in the intestine and spleen. Luciferase reporter assay demonstrated that nonanoic acid, capric acid (decanoic acid), undecanoic acid and lauric acid could inhibit cAMP signaling pathway and activate MAPK/ERK signaling pathway, while the potencies of these four fatty acids on the two signaling pathways were different. Lauric acid has the highest inhibitory potency on cAMP signaling pathway, followed by undecanoic acid, nonanoic acid, and capric acid. While for MAPK/ERK signaling pathway, nonanoic acid has the highest activation potency, followed by undecanoic acid, capric acid, and lauric acid. These findings lay the foundation for revealing the roles of different medium-chain fatty acids in the inflammatory response of common carp.

Biased agonists of GPR84 and insights into biological control.

GPR84 was first identified as an open reading frame encoding an orphan Class A G protein coupled receptor in 2001. Gpr84 mRNA is expressed in a limited number of cell types with the highest levels of expression being in innate immune cells, M1 polarised macrophages and neutrophils. The first reported ligands for this receptor were medium chain fatty acids with chain lengths between 9 and 12 carbons. Subsequently, a series of synthetic agonists that signal via the GPR84 receptor were identified. Radioligand binding assays and molecular modelling with site-directed mutagenesis suggest the presence of three ligand binding sites on the receptor, but the physiological agonist(s) of the receptor remain unidentified. Here, we review the effects of GPR84 agonists on innate immune cells following a series of chemical discoveries since 2001. The development of highly biased agonists has helped to probe receptor function in vitro, and the remaining challenge is to follow the effects of biased signalling to the physiological functions of innate immune cell types. LINKED ARTICLES: This article is part of a themed issue GPR84 Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.10/issuetoc.

MDSCs-derived GPR84 induces CD8+ T-cell senescence via p53 activation to suppress the antitumor response.

BACKGROUNDS: G-protein-coupled receptor 84 (GPR84) marks a subset of myeloid-derived suppressor cells (MDSCs) with stronger immunosuppression in the tumor microenvironment. Yet, how GPR84 endowed the stronger inhibition of MDSCs to CD8+ T cells function is not well established. In this study, we aimed to identify the underlying mechanism behind the immunosuppression of CD8+ T cells by GPR84+ MDSCs. METHODS: The role and underlying mechanism that MDSCs or exosomes (Exo) regulates the function of CD8+ T cells were investigated using immunofluorescence, fluorescence activating cell sorter (FACS), quantitative real-time PCR, western blot, ELISA, Confocal, RNA-sequencing (RNA-seq), etc. In vivo efficacy and mechanistic studies were conducted with wild type, GPR84 and p53 knockout C57/BL6 mice. RESULTS: Here, we showed that the transfer of GPR84 from MDSCs to CD8+ T cells via the Exo attenuated the antitumor response. This inhibitory effect was also observed in GPR84-overexpressed CD8+ T cells, whereas depleting GPR84 elevated CD8+ T cells proliferation and function in vitro and in vivo. RNA-seq analysis of CD8+ T cells demonstrated the activation of the p53 signaling pathway in CD8+ T cells treated with GPR84+ MDSCs culture medium. While knockout p53 did not induce senescence in CD8+ T cells treated with GPR84+ MDSCs. The per cent of GPR84+ CD8+ T cells work as a negative indicator for patients' prognosis and response to chemotherapy. CONCLUSIONS: These data demonstrated that the transfer of GPR84 from MDSCs to CD8+ T cells induces T-cell senescence via the p53 signaling pathway, which could explain the strong immunosuppression of GPR84 endowed to MDSCs.

Molecular Cloning, Tissue Distribution, and Pharmacological Characterization of GPR84 in Grass Carp (Ctenopharyngodon Idella).

The G-protein-coupled receptor GPR84, activated by medium-chain fatty acids, primarily expressed in macrophages and microglia, is involved in inflammatory responses and retinal development in mammals and amphibians. However, our understanding of its structure, function, tissue expression, and signaling pathways in fish is limited. In this study, we cloned and characterized the coding sequence of GPR84 (ciGPR84) in grass carp. A phylogenetic analysis revealed its close relationship with bony fishes. High expression levels of GPR84 were observed in the liver and spleen. The transfection of HEK293T cells with ciGPR84 demonstrated its responsiveness to medium-chain fatty acids and diindolylmethane (DIM). Capric acid, undecanoic acid, and lauric acid activated ERK and inhibited cAMP signaling. Lauric acid showed the highest efficiency in activating the ERK pathway, while capric acid was the most effective in inhibiting cAMP signaling. Notably, DIM did not activate GPR84 in grass carp, unlike in mammals. These findings provide valuable insights for mitigating chronic inflammation in grass carp farming and warrant further exploration of the role of medium-chain fatty acids in inflammation regulation in this species.

Kinetic insights into agonist-dependent signalling bias at the pro-inflammatory G-protein coupled receptor GPR84.

GPR84 is an orphan G-protein coupled receptor (GPCR) linked to inflammation. Strategies targeting GPR84 to prevent excessive inflammation in disease are hampered by a lack of understanding of its precise functional role. We have developed heterologous cell lines with low GPR84 expression levels that phenocopy the response of primary cells in a label-free cell electrical impedance (CEI) sensing system that measures cell morphology and adhesion. We then investigated the signalling profile and membrane localisation of GPR84 upon treatment with 6-OAU and DL-175, two agonists known to differentially influence immune cell function. When compared to 6-OAU, DL-175 was found to exhibit a delayed impedance response, a delayed and suppressed activation of Akt, which together correlated with an impaired ability to internalise GPR84 from the plasma membrane. The signalling differences were transient and occurred only at early time points in the low expressing cell lines, highlighting the importance of receptor number and kinetic readouts when evaluating signalling bias. Our findings open new ways to understand GPR84 signalling and evaluate the effect of newly developed agonists.

The GPR84 molecule is a mediator of a subpopulation of retinal microglia that promote TNF/IL-1α expression via the rho-ROCK pathway after optic nerve injury.

Resident microglia are important to maintain homeostasis in the central nervous system, which includes the retina. The retinal microglia become activated in numerous pathological conditions, but the molecular signatures of these changes are poorly understood. Here, using an approach based on FACS and RNA-seq, we show that microglial gene expression patterns gradually change during RGC degeneration induced by optic nerve injury. Most importantly, we found that the microglial cells strongly expressed Tnf and Il1α, both of which are known to induce neurotoxic reactive astrocytes, and were characterized by Gpr84high -expressing cells in a particular subpopulation. Moreover, ripasudil, a Rho kinase inhibitor, significantly blunted Gpr84 expression and cytokine induction in vitro and in vivo. Finally, GPR84-deficient mice prevented RGC loss in optic nerve-injured retina. These results reveal that Rho kinase-mediated GPR84 alteration strongly contribute to microglial activation and promote neurotoxicity, suggesting that Rho-ROCK and GPR84 signaling may be potential therapeutic targets to prevent the neurotoxic microglial phenotype induced by optic nerve damage, such as occurs in traumatic optic neuropathy and glaucoma.

Lipopolysaccharide Preconditioning Restricts Microglial Overactivation and Alleviates Inflammation-Induced Depressive-like Behavior in Mice.

Overactive microglia and severe neuroinflammation play crucial roles in the development of major depressive disorder. Preconditioning with lipopolysaccharide (LPS) provides protection against severe neuroinflammation. However, administering high doses of LPS to mice triggers depressive symptoms. Therefore, the optimal dose of LPS preconditioning needs to be determined by further experiments. LPS preconditioning is an effective agent in anti-inflammation and neuroprotection, but the mechanism by which LPS preconditioning acts in depression remain unclear. This study finds that the anti-inflammation mechanism of low-dose LPS preconditioning is mainly dependent on G-protein-coupled receptor 84 (GPR84). We use low-dose LPS for preconditioning and re-challenged mice or BV2 microglia with high-dose LPS. In addition, RNA-seq is used to explore underlying changes with LPS preconditioning. Low-dose LPS preconditioning reduces the expression of pro-inflammatory mediators and inhibits microglial activation, as well as suppresses the depressive-like behavior when the mice are re-challenged with high-dose LPS. Further investigation reveals that the tolerance-like response in microglia is dependent on the GPR84. Here, we show that low-dose LPS preconditioning can exert anti-inflammation effects and alleviates inflammation-induced depressive-like behavior in mice. As a potential therapeutic target for depression, LPS preconditioning needs to be given further attention regarding its effectiveness and safety.

Caprylic Acid (FFA C8:0) promotes the progression of prostate cancer by up-regulating G protein-coupled receptor 84/ Krüppel-like factor 7.

BACKGROUND: In previous study, we found that the content of medium-chain fatty acid Caprylic Acid (FFA C8:0) may be an important risk factor of obesity induced prostate cancer (PCa). However, the relationship between FFA C8:0 and PCa has not been reported. In this study, we explored whether the FFA C8:0 can promotes the progression of PCa by up-regulating Krüppel-like factor 7 (KLF7). METHODS: We collected tissues from PCa patients and Benign Prostate Hyperplasia (BPH), constructed a primary-tumor bearing mouse model with obesity through high-fat diet, and observed the tumor formation ability of PCa cells. In vitro, CCK8 assay, plate cloning, Transwell and scratch experiment were used to detect the changes in biological behavior of PCa cells stimulated by FFA C8:0. RESULTS: First, we found that the expression level of KLF7 is higher in PCa tissues of patients, and the expression of KLF7 is positively correlated with tumour-promoting gene IL-6, while it is negative correlated with another tumour-suppressor gene p21. Then, this study found that PCa cells were more likely to form tumors in diet induced obese mice. Compared with the normal diet group (ND), the expression levels of KLF7 in tumor tissues in high-fat diet group (HFD) were higher. Futhermore, we verified that high concentrations of FFA C8:0 can promote the biological behavior of PCa cells by activating KLF7/IL-6/p21 signaling pathway, which is mediated by the GPR84. CONCLUSIONS: Our research may provide a potential target for clinical prevention and treatment of PCa which induced by obesity.

GPR84 regulates pulmonary inflammation by modulating neutrophil functions.

Acute lung injury (ALI) is an acute, progressive hypoxic respiratory failure that could develop into acute respiratory distress syndrome (ARDS) with very high mortality rate. ALI is believed to be caused by uncontrolled inflammation, and multiple types of immune cells, especially neutrophils, are critically involved in the development of ALI. The treatment for ALI/ARDS is very limited, a better understanding of the pathogenesis and new therapies are urgently needed. Here we discover that GPR84, a medium chain fatty acid receptor, plays critical roles in ALI development by regulating neutrophil functions. GPR84 is highly upregulated in the cells isolated from the bronchoalveolar lavage fluid of LPS-induced ALI mice. GPR84 deficiency or blockage significantly ameliorated ALI mice lung inflammation by reducing neutrophils infiltration and oxidative stress. Further studies reveal that activation of GPR84 strongly induced reactive oxygen species production from neutrophils by stimulating Lyn, AKT and ERK1/2 activation and the assembly of the NADPH oxidase. These results reveal an important role of GPR84 in neutrophil functions and lung inflammation and strongly suggest that GPR84 is a potential drug target for ALI.

GPR84 potently inhibits osteoclastogenesis and alleviates osteolysis in bone metastasis of colorectal cancer.

The expression of GPR84 in bone marrow-derived monocytes/macrophages (BMMs) can inhibit osteoclast formation; however, its role in bone metastasis of colorectal cancer (CRC) is still unknown. To investigate the effects of GPR84 on bone metastasis of CRC, the murine CRC cell line MC-38 was injected into tibial bone marrow. We found that the expression of GPR84 in BMMs was gradually downregulated during bone metastasis of CRC, and the activation of GPR84 significantly prevented osteoclastogenesis in the tumor microenvironment. Mechanistically, the MAPK pathway mediated the effects of GPR84 on osteoclast formation. Moreover, we found that IL-11 at least partly inhibited the expression of GPR84 in the tumor microenvironment through the inactivation of STAT1. Additionally, activation of GPR84 could prevent osteolysis during bone metastasis of CRC. Our results suggest that CRC cells downregulate the expression of GPR84 in BMMs to promote osteoclastogenesis in an IL-11-dependent manner. Thus, GPR84 could be a potential therapeutic target to attenuate bone destruction induced by CRC metastasis.

Molecular characterization and functional exploration of GPR84 in Chinese Giant Salamander (Andrias davidianus).

The G protein-coupled receptor 84 (GPR84) is a putative medium-chain fatty acids (MCFAs) receptor involved in immune regulation and other metabolic processes. Most available studies focused on the GPR84 characterization from mammals, neglecting vital information that could be obtained from other levels of life, such as amphibians, necessary for an apt evolutionary understanding of the orphan GPR84. Hence, this study molecularly characterized and functionally explored the GPR84 from the Chinese Giant Salamander (Andrias davidianus). Therefore, we report that the Chinese Giant Salamander (CGS), one of the world's largest amphibians, expresses a GPR84 protein having 376 amino acids, with about 70% homologous to other amphibians and around 50% to human GPR84. Investigating the relative localized expression of gpr84 mRNA in CGS using quantitative PCR revealed the highest expression in the kidney and liver. Furthermore, four medium-chain fatty acids (MCFAs) at micromolar levels activated CGS-GPR84 transfected and expressed in HEK293 cells. In HEK293 cells, four different concentrations of MCFAs inhibited forskolin-induced cAMP accumulation and resulted in a dose-dependent increase in extracellular signal-regulated kinases 1 and 2 (ERK1/2). Interestingly, MCFAs activation of GPR84 concomitantly led to the upregulation of inflammatory mediators such as Nuclear Factor Kappa B (NF-κB) and IL-6. Conclusively, this study successfully elucidated the intriguing molecular and functional properties of CGS GPR84, particularly as an immune modulator, and has positioned the findings within the existing body of knowledge for a better overall understanding of GPR84, especially in amphibians.

Dietary Medium-Chain Triglyceride Decanoate Affects Glucose Homeostasis Through GPR84-Mediated GLP-1 Secretion in Mice.

Background: Dietary triglycerides are an important energy source; however, their excess intake causes metabolic diseases such as obesity and type 2 diabetes. Medium-chain triglycerides (MCTs) as triglyceride forms of medium-chain fatty acids (MCFAs) are applied to meet the energy demands of athletes, the elderly, and people with stunted growth, because MCFAs are efficiently converted into energy for immediate utilization by the organs and do not accumulate as fat. Although the intake of each MCT type (octanoate; C8:0, decanoate; C10:0, and dodecanoate; C12:0) exhibits beneficial metabolic effects, individual functional differences remain unclear. Methods: MCTs or MCFAs were administrated to male GPR84-deficient mice with a C57BL/6J background and mouse enteroendocrine cell line STC-1, and the effects on glucose homeostasis and gut hormone GLP-1 secretion were evaluated. Results: C10:0 intake improves glucose metabolism through the MCFA receptor GPR84-mediated GLP-1 secretion. Each MCT intake showed resistance to obesity and improved metabolic parameters compared with lard intake. Moreover, oral administration of MCTs enhanced glucose tolerance, especially C10:0 administration, which sufficiently increased plasma GLP-1 levels. Additionally, C10:0 stimulation promoted GLP-1 secretion via GPR84 in STC-1, enhanced glucose tolerance through GPR84-mediated GLP-1 secretion, and showed resistance to high-fat diet (HFD)-induced obesity in mice. Conclusions: Dietary MCT (C10:0) intake efficiently may protect against obesity and improve insulin resistance via GLP-1 secretion.