Melatonin And Melatonin Receptor Agonist Improve Oxidative Stress And Insulin Sensitivity In High-sucrose/High-fat Diet-fed Rats

Objective: To observe effects of weight gain, abdominal lipid deposition, oxidative stess and insulin sensitivity in SD rats fed by high-sucrose/ high-fat diet (HFSD); and to study whether the long-term administration of the melatonin (Mel) and melatonin receptor agonist(Tal) can inhibit obesity, decrease weight gain, lower the oxidative stress, and improve insulin sensitivity,thus protecting against the development of insulin resistance(IR).Methods: 1) Animal administration: 58 male Sprague Dawley rats weighing 150–200 g are randomized assigned to two dietary groups [n=10 in the normal control (CD) diet group, fed standard chow; n=48 in the high sucrose and high fat diet group, fed 53% normal diet supplemented with 10% lard and 37% sucrose]. All rats were fed for 6 months and treated for 2 months. The total study period was 8 months. The body weight of the rats were monitored every week. During the drug administration, normal control group were treated with intraperitoneal injection of physiological saline, Tal treated hyperglycemic groups with intraperitoneal injection of melatonin receptor agonist (0.1, 1 and 10mg/kg, respectively). 2) The levels of glucose and lipid plasma parameters were studied: blood samples for plasma parameters, including glucose, insulin, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), free fatty acid (FFA), oral glucose tolerant test (OGTT) and insulin sensitivity test, were withdrawn from the animals at the end of each month following an overnight fast. 3) The activities of antioxidative enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in blood were measured. The levels of lipid peroxidation products such as: malondialdehyde (MDA), which suggests the intensity of oxidative stress in pancreatic tissue, were measured. 4) Expression of mRNA levels of SOD, GSH-Px and CAT in adipocytes, liver and skeletal muscle are determined by Reverse Transcription-Polymerase Chain Reaction Analysis .Results: The insulin resistance was induced in SD rats by feeding high fat/high sucrose diet, levels of plasma fasting glucose, insulin, TG and FFA were increased; insulin sensitivity, HDL-C and the activities of antioxidative enzymes such as SOD, CAT and GSH-Px were markedly decreased. weight gain and abdominal lipid were increased. After administration of Mel and Tal with intraperitoneal injection, levels of plasma fasting glucose, insulin, TG, FFA, weight gain and abdominal lipid in those animals were significantly lowered; the level of malondialdehyde (MDA) in pancreatic tissue was also lowered; HDL-C and the activities of antioxidative enzymes were markedly increased; the expression of mRNA levels of GSH-Px, SOD and CAT in adipocytes, liver and skeletal muscle were also significantly increased. Tal and Mel increased the activities of SOD, GSH-Px, CAT and insulin sensitivity of peripheral tissues in SD rats.Conclusion:1. Tal and Mel significantly increased the activities of most antioxidative enzymes in liver, skeletal muscle and fat tissues, alleviated oxidative stress in tissues mentioned above in high-sucrose/ high-fat diet–fed SD rats.2. Tal and Mel can increase insulin sensitivity and improve insulin resistance in high-sucrose/ high-fat diet–fed SD rats.3. Mel and Tal can decrease weight gain and abdominal lipid deposition in high-sucrose/ high-fat diet–fed SD rat .