Background: Maternal obesity in rat leads to sympathetic mediated hypertension in the juvenile offspring and hyperphagia and increased adiposity in the adult offspring (1-2). We hypothesise that maternal obesity permanently influences the development of the melanocortin system in the offspring. Objective: To investigate the role of the melanocortin receptor 3 and 4 (MC3/4R) signaling, using a pharmacological intervention, on the development of juvenile sympathetic mediated hypertension, secondary to maternal obesity. Methods: Offspring of control (OffCon) and diet-induce obese dams (OffOb; at 23 or 172 days of age) were implanted with telemetry transmitter, inserted into the carotid artery in juvenile rats (DSI PhysioTel PA-C10) and abdominal aorta in adult rats (DSI PhysioTel PA-C40) under general anaesthesia (2% isofluorane). Pre and post-operative analgesia (Buprenorphine 0.1 mg/kg, intramuscular) was maintained for 24h. For drug i.c.v infusion, juvenile rats were anesthetized with ketamine (75 mg/kg, i.p) and domitor (0.5 mg/kg, i.p) and then placed in a stereotaxic frame. Cannula placement was made in the lateral ventricle (coordinates AP-0.9 mm, DV-3.5mm from bregma). MC3/4R antagonist (SHU9119, 1 nmol/h) or saline (Alzet osmotic pump; 0.5 ul/h, i.c.v) was chronically administrated for 7 days and body weight (BW), food intake (FI), mean arterial pressure (MAP) and heart rate (HR) recorded. After the experiments were completed, the rats were sacrificed with overdose of sodium pentobarbital, and their brain removed and sectioned to confirm accurate placement of the i.c.v cannula. At 6 months of age, MC4R agonist, Melanotan II (MTII, 2 mg/kg, i.p) and saline were injected and BW, FI, MAP and HR were recorded. Results: Juvenile OffOb rats showed an increased MAP prior to obesity. MC3/4R antagonism (SHU-9119) increased the BW and FI in OffOb relative to OffCon and elicited a greater decline in MAP (OffOb -29±4 mmHg versus OffCon, -12±3 mmHg, P<0.001, n=8). HR was lowered to the same extent in both groups. MTII treatment on the other hand increased HR to a greater extent in the OffOb versus OffCon without any significant difference in MAP response between groups. MTII was also more effective in reducing BW in the OffOb despite not having a differential effect on the FI. Conclusions: CNS melanocortin system contributes to the elevated MAP in OffOb and may play a key role in the early origin of sympathetic mediated hypertension. Increased signaling by the melanocortin receptor (MC3/4R) is also implicated in altered energy balance in this model.