Scientific Reports (2017-07-01)

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 Huo,
  • Fanyin Meng,
  • Gianfranco Alpini,
  • Pingwei Li,
  • Chaodong Wu

DOI
https://doi.org/10.1038/s41598-017-05884-y
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 13

Abstract

Read online

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.