cyclic-guanosine-monophosphate-adenosine-monophosphate and Obesity

Topics: Animals; Cyclic GMP; Diet, High-Fat; Hyperlipidemias; Inflammation; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Nucleotides, Cyclic; Obesity; Orlistat; Propolis; Rats; Rats, Sprague-Dawley; Signal Transduction; Vasodilation

It has been appreciated for many years that there is a strong association between metabolism and immunity in advanced metazoan organisms. Distinct immune signatures and signaling pathways have been found not only in immune but also in metabolic cells. The newly discovered DNA-sensing cGAS-cGAMP-STING pathway mediates type I interferon inflammatory responses in immune cells to defend against viral and bacterial infections. Recent studies show that this pathway is also activated by host DNA aberrantly localized in the cytosol, contributing to increased sterile inflammation, insulin resistance, and the development of nonalcoholic fatty liver disease (NAFLD). Potential interactions of the cGAS-cGAMP-STING pathway with mTORC1 signaling, autophagy, and apoptosis have been reported, suggesting an important role of the cGAS-cGAMP-STING pathway in the networking and coordination of these important biological processes. However, the regulation, mechanism of action, and tissue-specific role of the cGAS-cGAMP-STING signaling pathway in metabolic disorders remain largely elusive. It is also unclear whether targeting this signaling pathway is effective for the prevention and treatment of obesity-induced metabolic diseases. Answers to these questions would provide new insights for developing effective therapeutic interventions for metabolic diseases such as insulin resistance, NAFLD, and type 2 diabetes.

Topics: Apoptosis; Autophagy; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Interferon Type I; Mechanistic Target of Rapamycin Complex 1; Membrane Proteins; Non-alcoholic Fatty Liver Disease; Nucleotides, Cyclic; Nucleotidyltransferases; Obesity; Signal Transduction

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.

Topics: Adipocytes; Animals; Diet, High-Fat; Hepatocytes; Humans; Immunity, Innate; Interferon Type I; Macrophages; Membrane Proteins; Mice; Nucleotides, Cyclic; Obesity; Phosphorylation; Protein Serine-Threonine Kinases; Xanthones