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 (Adar1^+/-) mice were fed normal chow or a high-fat diet (HFD) for 12 wk. Adar1^+/- 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 Adar1^+/- improved HFD-induced dyslipidemia and insulin resistance. Metabolic studies showed that food intake was decreased in Adar1^+/- mice compared with the WT mice under HFD conditions. Paired feeding studies further demonstrated that Adar1^+/- protected mice from HFD-induced obesity through decreased food intake. Furthermore, Adar1^+/- 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.NEW & NOTEWORTHY 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.