Endocrine, metabolic and cardioprotective effects of hexarelin in obese Zucker rats

Abstract

Genetically obese male Zucker rats have an impaired secretion of GH, coupled to hyperinsulinemia, hyperlipidemia and glucose intolerance. The aim of this study was to evaluate whether a chronic treatment with hexarelin, a synthetic enkephalin-derived hexapeptide with a potent GH-releasing activity, might be able to ameliorate the somatotropic function and reverse some metabolic alterations associated with obesity in male obese Zucker rats. Furthermore, as decreased GH secretion and insulin resistance are associated with increased cardiovascular risk, we also tested the capacity of hexarelin to prevent postischemic ventricular dysfunction in hearts of male obese Zucker rats. Obese and lean male rats of the Zucker strain were treated with hexarelin (80 µg/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 days. An acute hexarelin injection (80 µg, s.c.) at the 28th day of treatment elicited a rise in plasma GH levels in lean but not in obese rats (pretreated or not with hexarelin); lean rats chronically treated with hexarelin showed a greater increase in plasma GH as compared with control counterparts. At the end of the experiment, pituitary GH mRNA levels were significantly reduced in obese rats and hexarelin administration failed to increase pituitary GH mRNA and IGF-I concentrations in plasma and heart. Chronic treatment with hexarelin increased insulinemia and blood glucose levels in obese but not in lean rats, left unaltered the high triglyceride levels but significantly decreased plasma cholesterol concentrations in obese rats. Heart preparations from lean and obese Zucker rats treated with saline, subjected to low flow ischemia and reperfusion, showed at reperfusion: a) a low recovery of postischemic left ventricular developed pressure (LVDP), coupled to a substantial increase in coronary perfusion pressure, and b) a marked increase in creatine kinase released in the perfusates. Hexarelin administration for 30 days counteracted the heart ischemic damage both in lean and obese Zucker rats. In fact, the recovery of LVDP at reperfusion was significantly higher than in controls and the increase in coronary resistance was minimal. Collectively, these data indicate that a 30-day treatment with hexarelin was unable to improve somatotropic function in male obese Zucker rats but was successful in decreasing plasma cholesterol concentrations. Hexarelin exerted a cardioprotective effect in both lean and obese rats. The heart-protective activity afforded by the peptide was divorced from any stimulation of the GH axis and is probably exerted through activation of specific cardiac receptors.

Thiazolidinedione Treatment Normalizes Insulin Resistance and Ischemic Injury in the Zucker Fatty Rat Heart

“…Plasma fatty acids and insulin resistance. The very high circulating levels of FFAs and TGs, with normal plasma glucose concentrations, are characteristic of the obese Zucker rat (5). Plasma insulin levels were not measured in the current study, but the development of insulin resistance in the absence of hyperglycemia is consistent with that in obese humans, in whom increased insulin levels moderate plasma glucose (42).…”

“…The obese Zucker rat, a highly dyslipidemic animal model of obesity and impaired glucose tolerance, shows little evidence of abnormal cardiac function when young (3)(4)(5) but has impaired cardiac function during hypoxia at 12 months of age (4). Insulin resistance in the obese rat heart has been associated with decreased GLUT4 glucose transporter protein content and impaired GLUT4 translocation to the sarcolemma (6,7).…”

Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases

“…The effect of hexarelin on blood insulin, glucose, and in general on type 2 diabetes mellitus has not been studied well yet. In one study, obese and lean male rats of the Zucker strain were treated with hexarelin (80 μg/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 days [111]. The results showed an increase in plasma insulin concentration in the obese rats treated with hexarelin.…”

“…Hexarelin through binding to CD36 receptor induced an increase in thermogenic coactivator PGC-1α and uncoupling protein-1 (UCP-1) in 3T3-L1 adipocytes as well as in epididymal fat of treated mice, indicating increased fatty acids metabolism in the white fat in response to hexarelin [70]. Hexarelin treatment in obese rats significantly decreased plasma cholesterol but not triglyceride levels [111]. In another study, apolipoprotein E-null mice maintained on a longterm, high-fat, and high-cholesterol diet, a condition known to cause atherosclerosis, showed a significant regression in atherosclerotic lesions when treated with hexarelin compared to saline-treated controls [136].…”

The Growth Hormone Secretagogue Hexarelin Protects Rat Cardiomyocytes From <i>in vivo</i> Ischemia/Reperfusion Injury Through Interleukin-1 Signaling Pathway

“…8) Hexarelin, a synthetic analog of ghrelin, shows effects similar to those of ghrelin and is more chemically stable, making it a potential alternative to ghrelin. Its beneficial action on the cardiovascular system has been reported by a lot of research, including inhibition of cardiomyocyte apoptosis, [9][10][11] anti-atherosclerosis, 12,13) improving cardiac output, [14][15][16][17] and suppressing cardiac fibrosis. 18) These effects are considered to be mediated not only by GHSR1a but also by activation of cardiac CD36 receptors.…”