The precise mechanism of action of semaglutide in obese patients remains uncertain, although it is evident that the drug confers a significant cardiac benefit. An excessively high-fat diet has been demonstrated to result in an increased expression of solute carrier family 27 member 2 (Slc27a2/FATP2) on cardiomyocyte membranes. This is associated with a number of adverse effects, including lipid deposition in cardiomyocytes, elevated levels of inflammation and oxidative stress, impaired cardiac function, decreased cardiomyocyte viability, and increased apoptosis. The administration of semaglutide was observed to partially reverse the cardiac dysfunction induced by an excessive high-fat diet, to protect cardiomyocytes, and to significantly reduce the expression of Slc27a2. However, the cardioprotective effects of semaglutide were partially counteracted by the use of an adenosine A2A receptor antagonist, whereas the opposite result was observed with an adenosine A2A receptor agonist. In light of these findings, it can be concluded that the adenosine A2A receptor plays a pivotal role in the cardioprotective effects of semaglutide. The reduction of Slc27a2 expression downstream of this receptor has been demonstrated to enhance lipid metabolism and mitigate lipid overdeposition in cardiomyocytes, thereby conferring cardioprotection.