Obstructive sleep apnoea, a syndrome leading to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but mechanisms of this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin- deficient obese C57BL/6J-Lep^ob mice. In lean mice, exposure to intermittent hypoxia for 5 days (short-term) resulted in a decrease in fasting blood glucose levels (from 173 ±11 mg/dl on day 0 to 138 ±10 mg/dl on day 5, p < 0.01), improvement in glucose tolerance without a change in serum insulin levels, and an increase in serum leptin levels in comparison with control (2.6 ±0.3 ng/ml vs. 1.7 ±0.2 ng/ml, p < 0.05). Microarray mRNA analysis in adipose tissue revealed that leptin was the only up-regulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 & [plusmn]136 % (p < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long-term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 ±1.1 ng/ml at baseline to 9.8 ±1.8 ng/ml at week 12, p < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.