<p>Metabolic syndrome weakens the cardioprotective effect of adaptation to chronic continuous hypoxia (CCH). Here we studied the relationship between this weakening and leptin receptor expression. Wistar rats were maintained on a high-fat high-carbohydrate diet for 84 days to model metabolic syndrome and subjected to CCH for 21 days at 12% O₂. Ischemia/reperfusion was modeled by occlusion of the left coronary artery (45 min) followed by reperfusion (2 h). The Ca²⁺-retention capacity of myocardial mitochondria was assessed. Metabolic syndrome increased leptin receptor expression in the myocardium by 46% and reduced the cardioprotective effect of CCH. Metabolic syndrome reduced Ca2+-retention capacity in both non-adapted and adapted to CCH rats. Leptin receptor expression showed an inverse correlation with Ca²⁺-retention capacity (<i>r =</i> -0.63, <i>p &lt;</i> 0.0001) and a direct correlation with the level of creatine kinase-MB (<i>r =</i> 0.32; <i>p =</i> 0.03). It is assumed that increased expression of leptin receptor in the myocardium of rats with metabolic syndrome plays an important role in weakening of the mechanisms of cardioprotective effects of adaptation to CCH.</p>