| Contributors: |
Wu, CD (reprint author), Texas A&M Univ, Dept Nutr & Food Sci, College Stn, TX 77843 USA.; Li, PW (reprint author), Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA.; Texas A&M Univ, Dept Nutr & Food Sci, College Stn, TX 77843 USA.; Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA.; Texas A&M Univ, Coll Med, Hlth Sci Ctr, Dept Mol & Cellular Med, College Stn, TX 77843 USA.; Chongqing Med Univ, Dept Endocrinol, Chongqing 400016, Peoples R China.; Chongqing Med Univ, Affiliated Hosp 1, Chongqing 400016, Peoples R China.; Chongqing Med Univ, Lab Lipid & Glucose Metab, Affiliated Hosp 1, Chongqing 400016, Peoples R China.; Univ North Dakota, Sch Med & Hlth Sci, Dept Pathol, Grand Forks, ND 58202 USA.; Augusta Univ, Vasc Biol Ctr, Dept Cellular Biol & Anat, Med Coll Georgia, Augusta, GA 30912 USA.; Peking Univ, Shenzhen Grad Sch, Key Lab Chem Genom, Drug Discovery Ctr, Shenzhen 518055, Peoples R China.; Texas A&M Univ, Hlth Sci Ctr, Dept Med Physiol, Temple, TX 76504 USA.; Texas A&M Univ, Dept Med, Hlth Sci Ctr, Temple, TX 76504 USA. |
| Description: |
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. ; National Institutes of Health [HL108922, HL095556, AI087741, DK095862, DK095828]; Welch Foundation [A-1816]; American Diabetes Association [1-17-IBS-145]; National Institutes of Food and Agriculture (NIFA); [DK095013] ; SCI(E) ; ARTICLE ; 7 |