Gender difference in the leptin response to feeding in peroxisome-proliferator-activated receptor-alpha knockout mice.OBJECTIVE:  Peroxisome-proliferator-activated receptor-alpha (PPARalpha) has a central role in lipid metabolism. Mice lacking PPARalpha accumulate hepatic fat and are prone to late onset obesity. Leptin, an adipocyte-derived hormone, also plays an important role in regulating energy balance. In order to test the hypothesis that leptin secretion increases in response to PPARalpha knockout, we determined leptin concentrations including the effect of nutritional status in male and female PPARalpha knockout mice compared with wild-type controls. DESIGN:  We studied the effect of 16 h fasting and 4 h refeeding on plasma leptin concentrations in male and female wild-type and PPARalpha-knockout mice, aged 14 weeks. In female mice the effect of daily growth hormone (GH) injection on the leptin response to refeeding was determined. RESULTS:  Circulating leptin concentrations were higher in female mice compared with males and increased in both sexes after PPARalpha-knockout. There was no change in leptin levels after a 16 h fast, compared with ad libitum feeding. However leptin increased with refeeding, to the greatest extent in female PPARalpha-knockout mice. Intermittent GH administration decreased leptin concentrations in female, wild-type and PPARalpha-knockout animals and abolished the exaggerated leptin response to refeeding. CONCLUSIONS:  Leptin concentrations are increased in PPARalpha-knockout mice. There are gender differences in the leptin response to feeding which may be due to differences in insulin sensitivity.