['High-fat diet (HFD)-induced hypertension in rabbits is neurogenic because of the central sympathoexcitatory actions of leptin. Hypothalamic melanocortin and neuropeptide Y (NPY) neurons are recognized as the major signalling pathways through which leptin exerts its central effects. In this study, we assessed the effects of specific antagonists and agonists to melanocortin and NPY receptors on HFD-induced sympathoexcitation and hypertension.', 'Rabbits were instrumented with intracerebroventricular cannula, renal sympathetic nerve activity (RSNA) electrode, and blood pressure telemetry transmitter.', 'After 3 weeks HFD (13.5% fat, n\u200a=\u200a12) conscious rabbits had higher RSNA (+3.8 \u200anu, P\u200a=\u200a0.02), blood pressure (+8.6\u200a mmHg, P\u200a<\u200a0.001) and heart rate (+15 \u200ab/min, P\u200a=\u200a0.01), and brain-derived neurotrophic factor levels in the hypothalamus compared with rabbits fed a control diet (4.2% fat, n\u200a=\u200a11). Intracerebroventricular administration of the melanocortin receptor antagonist SHU9119 reduced RSNA (-2.7 \u200anu) and blood pressure (-8.5 \u200ammHg) in HFD but not control rabbits, thus reversing 100% of the hypertension and 70% of the sympathoexcitation induced by a HFD. By contrast, blocking central NPY Y1 receptors with BVD10 increased RSNA only in HFD rabbits. Intracerebroventricular α-melanocortin stimulating hormone increased RSNA and heart rate (P\u200a<\u200a0.001) in HFD rabbits but had no effect in control rabbits.'] Does central proopiomelanocortin but not neuropeptide Y mediate sympathoexcitation and hypertension in fat fed conscious rabbits?