Title : Cyclic GMP-AMP: A new hope for metabolic disease?
Abstract:
Obesity is an ongoing pandemic which serves a causal factor of a wide range of metabolic diseases such as type 2 diabetes, non-alcoholic fatty liver disease, and atherosclerotic cardiovascular diseases. Accumulating evidence has suggested inflammation as a factor underlying the pathogenesis of obesity-associated metabolic diseases. To date, however, there is no reliable anti-inflammation-based therapy for metabolic diseases. Given this, there is a critical need to develop new and effective therapies for treatment of obesity-associated metabolic diseases. Over the past several years, cyclic GMP-AMP (cGAMP) has been identified as a dinucleotide that critically regulates innate immunity. Additionally, mitochondrial dysfunction pertinent to oxidation stress is shown to increase intracellular (endogenous) levels of cGAMP, which, in turn contributes to the development and progression of inflammation that causes insulin resistance and metabolic dysregulation. In contrast, treatment of obese mice with exogenous cGAMP results in amelioration of obesity-associated inflammation and improvement of systemic insulin resistance and aspects of diet-induced fatty liver disease. Specifically, in response to cGAMP treatment, high-fat diet (HFD)-fed C57BL/6J mice revealed a significant decrease in adipose tissue inflammation, evidenced by decreases in the phosphorylation states of JNK1 p46 and NFkB p65 and in the mRNA levels of proinflammatory cytokines. Moreover, treatment with exogenous cGAMP brought about significant improvement of systemic glucose homeostasis. These in vivo results were recapitulated by the results from cultured adipocytes, in which treatment with exogenous cGAMP decreased the proinflammatory responses and increased insulin signaling. Similarly, treatment with exogenous cGAMP significantly ameliorated HFD-induced hepatic fat deposition, through reducing the expression of lipogenesis-related genes, and decreased inflammation in the liver. In cultured primary mouse hepatocytes, treatment with exogenous cGAMP significantly increased the effect of insulin on inducing Akt phosphorylation and decreased the effect of palmitate on inducing fat deposition. In addition, treatment with exogenous cGAMP decreased the effect of lipopolysaccharides on stimulating proinflammatory signaling pathway through JNK in mouse primary hepatocytes. Taken together, these findings validate that exogenous cGAMP exerts anti-inflammatory effects, which is different from endogenous cGAMP. Additionally, exogenous cGAMP is capable of enhancing systemic insulin sensitivity and metabolic homeostasis, which is attributable to improving inflammatory and metabolic responses of adipose and liver tissues. As such, the anti-inflammatory, anti-steatotic, and insulin-sensitizing effects of exogenous cGAMP warrant future studies to develop cGAMP mimic(s) as novel therapy for obesity- associated metabolic diseases.
