Adenosine Monophosphate Improves Lipolysis in Obese Mice by Reducing DNA Methylation via ADORA2A Activation by Ecto‐5′‐Nucleotidase (CD73)

Abstract The previous work discovers the potential of adenosine monophosphate (AMP) to alleviate obesity‐related metabolic diseases, but the underlying molecular mechanisms remain incompletely understood. Here, AMP is confirmed to enhance white fat decomposition and improve abnormal glucose and lipid metabolism in mice fed with a high‐fat (HF) diet. Mechanically, AMP is converted to adenosine (ADO) through ecto‐5′‐nucleotidase (CD73), and adenosine A2A receptor (ADORA2A) signaling activation is involved in the down‐regulation of methylation in white adipose tissue, thereby reducing the hormone‐sensitive lipase (HSL) methylation level and promoting HSL transcription and white fat decomposition. Moreover, the metabolic benefits of AMP are found to be partially eliminated in ADORA2A knockout mice, but re‐expression of ADORA2A can reproduce the AMP‐induced metabolic regulation in white fat. These findings reveal the mechanism that AMP, as the upstream of ADO, stimulates ADORA2A signaling and white fat DNA methylation to participate in the anti‐obesity effect.