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

Xin Guo,Ke K Zhang,Honggui Li,Yuli Cai,Chen Lü ,Ting Guo,Mengyang Li ,Rachel Botchlett,Chen Shu ,Juan Zheng,Pingwei Li,Qifu Li,Huaxi Xu ,Ya Pei,Gianfranco Alpini,Fanyin Meng,Yuqing Huo,Xinsheng Gao,Linglin Xie,Shih Lung Woo ,Jun Ji ,Jing Zhou,Xiaoqiu Xiao,Chaodong Wu

doi:10.1038/s41598-017-05884-y

Xin Guo, Ke K Zhang + Show 22 more

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https://doi.org/10.1038/s41598-017-05884-y

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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.

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Accumulating evidence demonstrates an essential role for the innate immune system in regulating metabolic homeostasis
Using approaches involving myeloid cell-specific gene disruption and/or bone marrow transplantation, a number of regulators such as peroxisome proliferator-activated receptor gamma (PPARγ), Jun-N terminal kinase 1 (JNK1), Toll-like receptor 4 (TLR4), Period (Per)1/Per[2], and hypoxia-inducible factor (HIF)-2α are shown to alter the inflammatory status of macrophages, which in turn interact with metabolic cells, i.e., hepatocytes and adipocytes, to maintain glucose homeostasis physiologically or to contribute to glucose dysregulation pathologically[8,9,10,11,12]
Using diet-induced obesity (DIO) mice, we demonstrated that treatment with exogenous Cyclic GMP-AMP (cGAMP) suppresses diet-induced inflammatory responses in both the liver and adipose tissue and improves systemic and local metabolic responses

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Accumulating evidence demonstrates an essential role for the innate immune system in regulating metabolic homeostasis. Using approaches involving myeloid cell-specific gene disruption and/or bone marrow transplantation, a number of regulators such as peroxisome proliferator-activated receptor gamma (PPARγ), Jun-N terminal kinase 1 (JNK1), Toll-like receptor 4 (TLR4), Period (Per)1/Per[2], and hypoxia-inducible factor (HIF)-2α are shown to alter the inflammatory status of macrophages, which in turn interact with metabolic cells, i.e., hepatocytes and adipocytes, to maintain glucose homeostasis physiologically or to contribute to glucose dysregulation pathologically[8,9,10,11,12] These findings demonstrate the importance of the innate immune system, in particular macrophages, in controlling metabolic homeostasis. We summarize our analyses suggesting novel and essential roles of exogenous cGAMP in regulating innate immunity and metabolic homeostasis

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