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Obesity is a disease of the energy homeostasis system, not merely a passive accumulation of fat. The hypothalamus serves as the regulatory center for energy balance, and together with peripheral organs, such as liver, pancreas, muscle and adipose tissue, controls food intake, energy expenditure, and whole-body metabolism. Adenosine, a product of ATP catabolism, exerts its effects through various G-protein-coupled receptors: A1R, A2AR, A2BR, and A3R. It plays a key role in regulating peripheral metabolism, including glucose homeostasis, insulin sensitivity, fat beta-oxidation, and lipolysis in adipose tissue. Beyond its roles in the CNS, adenosine receptors are also crucial in metabolic tissues, where they regulate glucose and lipid homeostasis and contribute to overall metabolic function. Several studies have been analyzing the role of adenosine system, specifically the adenosine receptors in the regulation of whole-body metabolism, and the importance of adenosine receptors in context of metabolic diseases and obesity. In this review, we provide an overview of the adenosine signaling system, highlighting its role in metabolic regulation as well as the pathophysiological mechanisms underlying obesity and type 2 diabetes.<\/jats:p>","DOI":"10.3390\/diabetology6050043","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T11:54:26Z","timestamp":1747655666000},"page":"43","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Role of Adenosine Signaling in Obesity-Driven Type 2 Diabetes: Revisiting Mechanisms and Implications for Metabolic Regulation"],"prefix":"10.3390","volume":"6","author":[{"given":"Giuseppe","family":"Faraco","sequence":"first","affiliation":[{"name":"Laboratory of Neuroimmune-Metabolism, Federal University of Santa Catarina, Florian\u00f3polis 88037-000, SC, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3151-4234","authenticated-orcid":false,"given":"Joana M.","family":"Gaspar","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroimmune-Metabolism, Federal University of Santa Catarina, Florian\u00f3polis 88037-000, SC, Brazil"},{"name":"Graduate Program in Biochemistry, School of Biological Sciences, Federal University of Santa Catarina, Florian\u00f3polis 88037-000, SC, Brazil"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,19]]},"reference":[{"key":"ref_1","unstructured":"World Obesity Federation (2023). 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