ADAR1 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice.

Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases, and many other chronic diseases. The objective of this study was to determine the role of adenosine deaminase acting on RNA 1 (ADAR1) in the development of obesity and insulin resistance. Wild-type (WT) and heterozygous ADAR1-deficient () mice were fed normal chow or a high-fat diet (HFD) for 12 wk. mice fed with HFD exhibited a lean phenotype with reduced fat mass compared with WT controls, although no difference was found under chow diet conditions. Blood biochemical analysis and insulin tolerance test showed that improved HFD-induced dyslipidemia and insulin resistance. Metabolic studies showed that food intake was decreased in mice compared with the WT mice under HFD conditions. Paired feeding studies further demonstrated that protected mice from HFD-induced obesity through decreased food intake. Furthermore, restored the increased ghrelin expression in the stomach and the decreased serum peptide YY levels under HFD conditions. These data indicate that ADAR1 may contribute to diet-induced obesity, at least partially, through modulating the ghrelin and peptide YY expression and secretion. This study identifies adenosine deaminase acting on RNA 1 as a novel factor promoting high-fat diet-induced obesity, at least partially, through modulating appetite-related genes ghrelin and PYY.