Background: Fatty acid mobilization and inflammatory response of adipose tissues vary in various depots, hence the response of fat-tailed and thin-tailed sheep breeds to different energy balances was hypothesized to be different due to differences in proportion and metabolism of various adipose depots in these breeds which may affect whole body insulin sensitivity. Objective: Current study aimed to evaluated the changes in plasma metabolites including non-esterified fatty acid (NEFA), glucose, insulin, triglyceride (TG) and tumor necrosis factor-alpha in response to negative and positive energy balances and their correlation with insulin sensitivity indexes in Lori-Bakhtiari fat-tailed and Lori-Bakhtiari × Romanov cross breed thin-tailed lambs. Methods: Thirty-six male lambs (18 fat-tailed and 18 thin-tailed lambs) were placed in individual pens and experienced periods of negative (21 d) and positive (21 d) energy balances. Lambs were bled weekly to measure plasma metabolites. Pearson correlation coefficients among variables were generated using Proc Corr of SAS. Results: In thin-tailed but not fat-tailed lambs, plasma NEFA showed a negative correlation with plasma glucose (R = -0.47; P < 0.0003) and insulin (R = -0.46; P < 0.0005) content. Plasma NEFA negatively correlated with revised quantitative insulin sensitivity check index (RQUICKI) and severity of the correlation was higher in fat-tailed (R = -0.58; P < 0.0001) comparing to thin-tailed (R = -0.40; P < 0.003) lambs. In fat-tailed lambs, plasma NEFA and insulin were the most influential factors on RQUICKI, whereas in thin-tailed lambs, insulin was the main factor affecting RQUICKI. Conclusion: The results of current study demonstrate that despite higher basal and negative energy balance induced plasma NEFA content in thin-tailed lambs, the contribution of plasma NEFA to insulin resistance was higher in fat-tailed lambs, whereas negative correlation between plasma NEFA and insulin content in thin-tailed lambs demonstrate higher sensitivity of insulin secretion capacity to plasma NEFA content.