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

Xin Guo, Chang Shu, Honggui Li, Ya Pei, Shih Lung Woo, Juan Zheng, Mengyang Liu, Hang Xu, Rachel Botchlett, Ting Guo, Yuli Cai, Xinsheng Gao, Jing Zhou, Lu Chen, Qifu Li, Xiaoqiu Xiao, Linglin Xie, Ke K. Zhang, Jun Yuan Ji, Yuqing HuoFanyin Meng, Gianfranco Alpini, Pingwei Li, Chaodong Wu

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6 Scopus citations

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.

Original languageEnglish (US)
Article number6355
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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    Guo, X., Shu, C., Li, H., Pei, Y., Woo, S. L., Zheng, J., Liu, M., Xu, H., Botchlett, R., Guo, T., Cai, Y., Gao, X., Zhou, J., Chen, L., Li, Q., Xiao, X., Xie, L., Zhang, K. K., Ji, J. Y., ... Wu, C. (2017). Cyclic GMP-AMP Ameliorates Diet-induced Metabolic Dysregulation and Regulates Proinflammatory Responses Distinctly from STING Activation. Scientific reports, 7(1), [6355]. https://doi.org/10.1038/s41598-017-05884-y