Abstract
Melatonin treatment has been shown to prevent the harmful effects of diet-induced obesity and reduce myocardial susceptibility to ischaemia-reperfusion injury (IRI) when administered from the onset of obesity. However, the exact mechanism whereby it exerts its beneficial actions on the heart in obesity and insulin resistance is unknown. In this study we investigated the effects of relatively short-term melatonin treatment on the heart in a rat model of diet-induced obesity. Control (C) and diet-induced obese (D) Wistar rats (fed for 20 weeks (wks)) were divided into 3 groups receiving drinking water with or without melatonin (4mg/kg/day) for the last 6 or 3 wks of experimentation. Isolated hearts were perfused in the working mode, subjected to regional (35min) or global ischaemia (15min) and reperfusion (2h); others were non-perfused (baseline). Myocardial infarct sizes as well as baseline and post-ischaemic activation of PKB/Akt, ERK42/44, GSK-3β and STAT-3 were determined. Blood was collected for study of metabolic parameters. Diet-induced obesity caused significant increases in body weight gain (14.5%), visceral adiposity (70.3%), fasting blood glucose (20%), serum insulin (55.6%) and triglyceride (84.2%) levels with a concomitant increase in post-ischaemic myocardial infarct size (41%) and a reduced cardiac output (12.7%). Melatonin treatment (both 3 and 6 wks) decreased serum insulin levels and the HOMA-index in the D group only (3 wks % reduction: 39%; 47.2%, p<0.05 vs untreated D respectively) with no effect on body weight gain, visceral adiposity, serum triglycerides and glucose levels. It also increased serum adiponectin levels in the D group (113% p<0.05 vs untreated D), reduced myocardial infarct sizes in both groups (3 wks %reduction: C 42.4%; D 61.6%) and activated baseline myocardial STAT-3, PKB/Akt, ERK42/44 and GSK-3β after 10 min reperfusion. Short-term melatonin administration to obese and insulin resistant rats reduced insulin resistance and protected the heart against ex vivo myocardial IRI independently of body weight gain and visceral adiposity. Melatonin-induced cardioprotection was associated with concomitant activation of the RISK and SAFE pathways.
Published Version
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