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Cyclic GMP-AMP Ameliorates Diet-induced Metabolic Dysregulation and Regulates Proinflammatory Responses Distinctly from STING Activation.

ABSTRACT: Endogenous cyclic GMP-AMP (cGAMP) binds and activates STING to induce type I interferons. However, whether cGAMP plays any roles in regulating metabolic homeostasis remains unknown. Here we show that exogenous cGAMP ameliorates obesity-associated metabolic dysregulation and uniquely alters proinflammatory responses. In obese mice, treatment with cGAMP significantly decreases diet-induced proinflammatory responses in liver and adipose tissues and ameliorates metabolic dysregulation. Strikingly, cGAMP exerts cell-type-specific anti-inflammatory effects on macrophages, hepatocytes, and adipocytes, which is distinct from the effect of STING activation by DMXAA on enhancing proinflammatory responses. While enhancing insulin-stimulated Akt phosphorylation in hepatocytes and adipocytes, cGAMP weakens the effects of glucagon on stimulating hepatocyte gluconeogenic enzyme expression and glucose output and blunts palmitate-induced hepatocyte fat deposition in an Akt-dependent manner. Taken together, these results suggest an essential role for cGAMP in linking innate immunity and metabolic homeostasis, indicating potential applications of cGAMP in treating obesity-associated inflammatory and metabolic diseases.

SUBMITTER: Guo X

PROVIDER: S-EPMC5526935 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway play a significant role in the production of inflammatory cytokines and type I interferons. This study aims to develop a cGAS-STING pathway-related genes (CSRs) prediction model to predict prognosis in gastric cancer (GC). In the present study, we used The Cancer Genome Atlas (TCGA), Gene Expression Omnibus databases (GEO), CIBERSORT and Tumor Immune Estimation Resource databases (TIMER). The risk model based on five hub genes (IFNB1, IFNA4, IL6, NFKB2, and TRIM25) was constructed to predict the overall survival (OS) of GC. Further univariate Cox regression (URC) and multivariate Cox regression (MCR) analyses revealed that this risk scoring model was an independent factor. The results were verified by GEO external validation set. Multiple immune pathways were assessed by Gene Set Enrichment Analysis (GSEA). TIMER analysis demonstrated that risk score strongly correlated with Macrophage, B cells and CD8 + T cells infiltration. In addition, through 'CIBERSORT' package, the higher levels of infiltration of T cell follicular assistance (P = 0.011), NK cells-activated (P = 0.034), and Dendritic cells resting (P = 0.033) exhibited in high-risk group. Kaplan-Meier (K-M) survival analysis illustrated T cells CD4 memory resting and T cells follicular helper infiltration correlated with overall survival (OS) of GC patients in TCGA and GEO databases. Altogether, the risk score model can be conveniently used to predict prognosis. The immunocyte infiltration analysis provided a novel horizon for monitoring the status of the GC immune microenvironment.Abbreviations:TCGA: The Cancer Genome Atlas databases; GEO: Gene Expression Omnibus databases; GC: Gastric cancer; CSRs: cGAS-STING pathway-related genes; DECSRs: Differential expressed cGAS-STING pathway-related genes; PCSRs: Prognosis related cGAS-STING pathway genes; URC: Univariate Cox regression analyses; MCR: Multivariate Cox regression analyses GSEA: Gene set enrichment analysis; TIIC: Tumor-infiltrating immune cell.

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Cyclic GMP-AMP Ameliorates Diet-induced Metabolic Dysregulation and Regulates Proinflammatory Responses Distinctly from STING Activation.

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