Abstract

Objective: We recently showed that leptin has powerful CNS-mediated antidiabetic and cardiovascular actions. This study tested whether the CNS melanocortin system mediates these actions of leptin in diabetic rats.

Research design and methods: A cannula was placed in the lateral ventricle of Sprague-Dawley rats for ICV infusions, and arterial and venous catheters were implanted to measure arterial pressure (MAP) and heart rate (HR) 24-h/d and for IV infusions. After recovery from surgery for 8 days, rats were injected with streptozotocin (STZ) and 5 days later either saline or the melanocortin 3 and 4 receptor (MC3/4R) antagonist, SHU-9119 (1 nmol/hr), was infused ICV for 17 days. Seven days after starting the antagonist, leptin (0.62 μg/hr) was added to the ICV infusion for 10 days. Another group of diabetic rats was infused with the MC3/4R agonist, MTII (10 ng/hr, ICV), for 12 days, followed by 7 days at 50 ng/hr.

Results: Induction of diabetes caused hyperphagia, hyperglycemia, and decreases in HR (-76 bpm) and MAP (-7 mmHg). Leptin restored appetite, blood glucose (BG), HR and MAP back to pre-diabetic values in vehicle treated rats, whereas it had no effect in SHU-9119 treated rats. MTII infusions transiently reduced BG and raised HR and MAP, which returned to diabetic values 5-7 days after starting the infusion.

Conclusions: Although a functional melanocortin system is necessary for the CNS-mediated antidiabetic and cardiovascular actions of leptin, chronic MC3/4R activation is apparently not sufficient to mimic these actions of leptin which may involve interactions of multiple pathways.