Sibutramine reduces feeding, body fat and improves insulin resistance in dietary-obese male Wister rats independently of hypothalamic neuropeptide Y

1 We studied the effects of the novel noradrenaline and serotonin (5-HT) reuptake inhibitor sibutramine on feeding and body weight in a rat model of dietary obesity, and whether it interacts with hypothalamic neuropeptide Y (NPY) neurones. 2 Chow-fed and dietary-obese (DIO) male Wistar rats were given sibutramine (3 mg kg(-1) day(-1) p.o.) or deionized water for 21 days. 3 Sibutramine decreased food intake throughout the treatment period in both dietary-obese rats (P < 0.0001) and lean rats (P < 0.0001). Weight gain was reduced so that final body weight was 10% lower in dietary-obese (P < 0.005) and 8% lower in lean (P < 0.05) rats versus their untreated controls. Plasma leptin concentration was lower in sibutramine-treated dietary-obese rats (P < 0.05), and in treated lean rats (P < 0.05). Using the homeostasis model assessment (HOMA) as a measure of insulin resistance, untreated DIO rats were significantly more insulin resistant than controls (P < 0.005), and this was corrected by sibutramine treatment (P < 0.05). Neither hypothalamic NPY mRNA nor NPY peptide levels in a number of hypothalamic nuclei were significantly altered by sibutramine compared to untreated controls. 4 The hypophagic and anti-obesity effects of sibutramine in dietary-obese Wistar rats appear not to be mediated by inhibition of ARC NPY neurones.