Sinalização purinérgica na obesidade: mecanismos inflamatórios e perspectivas terapêuticas

Abstract

Obesity is currently recognized as a complex chronic disease associated with a persistent state of low-grade chronic inflammation, which contributes to the progression of several systemic complications. In this context, purinergic signaling has emerged as an important mechanism involved in regulating the inflammatory response in adipose tissue, acting directly in the communication between adipocytes, immune cells, and inflammatory mediators. This review discusses the role of purinergic signaling in the inflammatory pathophysiology of obesity, emphasizing the participation of extracellular nucleotides, purinergic receptors, and ectonucleotidases in the maintenance of metaflammation. Under conditions of adipocyte hypertrophy, hypoxia, and cellular stress, there is an increase in extracellular ATP release, which acts as a danger signal and promotes the activation of pro-inflammatory receptors, especially P2X7 and P2Y6. The activation of these receptors stimulates inflammasome assembly, intensifies the release of pro-inflammatory cytokines, and promotes the recruitment and activation of inflammatory macrophages in adipose tissue, contributing to the perpetuation of chronic inflammation. In contrast, the enzymes Ectonucleoside Triphosphate Diphosphohydrolase-1 (CD39) and Ecto-5’-Nucleotidase (CD73) convert ATP into adenosine, a molecule associated with the suppression of inflammation through the activation of A2A and A2B receptors. However, obesity is associated with increased adenosine deaminase (ADA) activity, reducing adenosine availability and impairing its anti-inflammatory effects. Therefore, antagonists of P2X7 and P2Y6 receptors, agonists of A2A receptors, and interventions targeting CD39, CD73, and ADA emerge as promising therapeutic strategies to reduce adipose tissue inflammation and limit the progression of obesity-related complications.