Obesogenic effect of high-fat (HF) diet can be counterbalanced by stimulation of energy expenditure and lipid oxidation in response to the meal. Aim of this study was to reveal whether muscle nonshivering thermogenesis could be stimulated by HF diet. The other aim was to support the hypothesis of leptin and AMP-activated protein kinase (AMPK) involvement in this mechanism. Male mice of obesity-resistant A/J and obesity-prone B/6J strains, born and maintained at 30 ^oC, were used. At 4 weeks of age, mice were randomly weaned onto a low-fat (LF) or HF diet. At the age of 6 weeks, indirect calorimetry and cold tolerance test were performed and tissues for in-vitro experiments, biochemical and gene expression analysis were collected. The A/J LF mice were cold-sensitive, while the A/J HF, B/6J LF and B/6J HF mice were cold-tolerant. Cold-sensitivity of the A/J LF mice was associated with low energy expenditure, which was normalized by HF diet. Only in A/J mice, oxygen consumption, total content and phosphorylation of AMPK, and AICAR-stimulated palmitate oxidation in soleus muscle was increased by the HF diet in parallel with significantly increased leptinemia. Gene expression data in soleus muscle of the A/J HF mice indicate a shift from carbohydrate to lipid oxidation. Our results suggest a role of muscle nonshivering thermogenesis and lipid oxidation in the obesity-resistant phenotype of A/J mice and indicate that HF diet could induce thermogenesis in oxidative muscle, possibly by the leptin-AMPK axis.