A functional melanocortin system is required for the CNS actions of leptin on peripheral glucose regulation and cardiovascular function

Abstract

We showed that leptin has powerful CNS effects that increase MAP and HR while reducing food intake (FI) and markedly lowering glucose levels (BG) even when insulin is reduced to very low levels by streptozotocin (STZ) injection. This study tested whether the melanocortin system mediates the cardiovascular, appetite and metabolic actions of leptin in insulin-deficient diabetes. A cannula was placed in the lateral ventricle of male SD rats for ICV infusions, arterial and venous catheters were implanted to measure MAP and HR 24 h/d and IV infusions. Five days after STZ injection, rats were infused with melanocortin 3 and 4 receptor (MC3/4R) antagonist, SHU-9119 (1 mmol/hr, ICV), for 17 days. Seven days after starting the antagonist, leptin was added to the ICV infusion at 1.2 μg/kg/hr for 10 days. Another group of diabetic rats was infused ICV with MC3/4R agonist, MTII, for 12 days at 10 ng/hr, followed by 7 days at 50 ng/hr. After induction of diabetes, FI increased 50%, BG increased from ~120 to ~440 mg/dl, HR and MAP decreased by 76 bpm and 7 mmHg. HR continued to decrease (−50 bpm) and FI to increase (+50%) during the first 7 days of MC3/4R blockade, MAP and BG remained constant. SHU-9119 treatment prevented leptin's effect to reduce FI and BG (430 mg/dl at the end of leptin infusion) and to raise HR and MAP. MTII infusion at regular or high doses transiently reduced FI and BG levels and raised HR and MAP, which gradually returned to diabetic values 5 to 7 days after starting the infusion. Thus, a functional melanocortin system is necessary for the CNS actions of leptin in regulating glucose homeostasis and cardiovascular function in type-1 diabetes. However, the effects of excessive MC3/4R activation can be offset by compensatory mechanisms normally suppressed by leptin. (NHLBI HL51971, AHA)