Abstract 561: Melanocortin-4 Receptor Signaling Is Required For The Anorexic, Cardiovascular And Antidiabetic Actions Of Leptin In Diabetic Rats.

Abstract

We previously demonstrated that leptin has powerful antidiabetic actions that are mediated mainly through central nervous system (CNS) effects. In this study we tested the specific importance of melanocortin-4 receptor (MC4R) in mediating leptin’s ability to suppress food intake, to increase blood pressure (BP) and heart rate (HR), and to normalize glucose levels in insulin-dependent diabetes. MC4R knockout (MC4R -/- , n=5) and control wild-type rats (WT, n=4) were implanted with BP telemetry transmitters and an intracerebroventricular (ICV) cannula was inserted into the brain lateral ventricle. After 10 days of recovery, BP and HR were measured 24-hrs/day. After stable baseline measurements for 5 days, a single bolus injection of streptozotocin (STZ) (50 mg/kg, ip) was used to induce insulin-dependent diabetes. Eight days after STZ injection, an osmotic pump was implanted subcutaneously and connected to the ICV cannula to deliver leptin (15 μg/day) for 7 days. At baseline, MC4R -/- rats ate 20% more and were 40% heavier than WT rats. Despite being markedly obese, BP was similar (112±2 vs. 111±2 mmHg) and HR was lower in MC4R -/- rats (320±6 vs. 347±5 bpm). Induction of diabetes increased food intake (30%) and reduced BP (~17 mmHg) and HR (~61 bpm) in WT rats, while food intake, BP and HR were reduced by ~10%, 7 mmHg and 33 bpm in MC4R -/- rats. Leptin treatment for 7 days normalized glucose levels (437±10 to 136±18 mg/dl), reduced food intake (40%), and increased HR (+60 bpm) and BP (+9 mmHg) in WT rats. However, only modest changes in glucose levels (367±16 to 326±23 mg/dl), food intake (5%), HR (+16 bpm) and BP (+4 mmHg) were observed in MC4R -/- rats. These results indicate that intact CNS MC4R signaling is necessary for leptin to exert its chronic anorexic, cardiovascular and antidiabetic actions.