Leptin is thought to play a significant role in energy balance as an afferent signal to the hypothalamus that reflects body fat content. In addition, leptin may also act as an acute sensor of energy balance independent of body fat mass, since ob gene expression and plasma leptin concentrations are decreased in lean animals and humans in response to short-term caloric deprivation. However, in obese animals and humans, the acute response of leptin to fasting is less clear. We investigated the effects of a 24-hour fast on circulating plasma leptin concentrations in lean and obese Psammomys obesus (Israeli sand rats). In the lean, insulin-sensitive group (n = 25) a 24-hour fast caused a 44% decrease in plasma leptin, whereas in the obese, insulin-resistant group (n = 24) plasma leptin increased by 18% after fasting (P < .003). There was no difference between the two groups regarding the effect of a 24-hour fast on body weight, blood glucose, or plasma insulin. Within the insulin-resistant group, there was no difference in the response of leptin to fasting between hyperglycemic and normoglycemic animals. We conclude that there is a dysregulation of leptin in response to acute caloric deprivation in obese, insulin-resistant but not in lean, insulin-sensitive P obesus.