NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulin sensitivity in high-fat/high-sucrose-fed rats

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Abstract

Evidences indicate that a complex relationship exists among sleep disorders, obesity and insulin resistance. NEU-P11 is a novel melatonin agonist used in treatment of psychophysiological insomnia, and in animal studies NEU-P11 showed sleep-promoting effect. In this study, we applied NEU-P11 on obese rats to assess its potential melatoninergic effects in vivo. Obese models were established using high-fat/high-sucrose-fed for 5 months. NEU-P11 (10 mg/kg)/melatonin (4 mg/kg)/vehicle were administered by a daily intraperitoneal injection respectively for 8 weeks. Our results showed that NEU-P11 or melatonin inhibited both body weight gain and deposit of abdominal fat with no influence on food intake. The impaired insulin sensitivity and antioxidative potency were improved and the levels of plasma glucose, total cholesterol (TC), triglycerides (TG) decreased with an increased in HDL-cholesterol (HDL-c) after NEU-P11 or melatonin administration. These data suggest that NEU-P11, like melatonin, decreased body weight gain and improved insulin sensitivity and metabolic profiles in obese rats. We conclude that NEU-P11 has a melatoninergic effect on regulating body weight in obese rats and also improving metabolic profiles and efficiently enhancing insulin sensitivity.

Introduction

Obesity is reaching epidemic proportions worldwide and is increasing at an alarming rate. This is being driven, at least in part, by the westernization of diet with high-fat and higher caloric intake [1]. Obesity related disorders, such as insulin resistance, type 2 diabetes, hypertension and atherosclerosis diseases, are placing a considerable strain on our healthcare system [2], [3], [4]. Furthermore, recent evidence suggests an association between overweight, obesity and sleep disorders. For example, subjects with sleep disorders have an increased risk of obesity [5] and overweight and obese participants report sleeping less than subjects with a normal BMI [6]. On the other hand, overwhelming evidence supports the link between sleep disorder and risk of insulin resistance and diabetes [1], [7], [8], [9], [10]. On the base of these studies, Spiegel et al. [11] concludes correlation amongst weight gain, insulin resistance, type 2 diabetes and sleep disorders in a recent review.

The prevalence of obesity and obesity related metabolic and sleep disorders emphasizes the need for concerted efforts to prevent obesity rather than just treatment of its associated diseases, and there is a significant need for new drugs that effectively manage obesity, insulin resistance and sleep disorder while minimizing the risk of significant adverse effects.

Melatonin, a neurohormone synthesized and secreted at night mainly by the pineal gland in vertebrates, is known for its sleep-promoting effects, which include shortening of sleep latency and lengthening of sleep duration [12]. On the other hand, several reports indicate that melatonin affects food intake, adiposity and BW in some species, although such effects are highly variable, including decrease in fat mass and BW in Siberian hamster [13], rats [14], [15], [16], [17] and goldfish [18], increase in gray mouse lemurs [19] and raccoon dog [20] and no modifications in rat or in vole [21], [22]. Melatonin also influences liver, kidney, and muscle energy contents of mammals [23], [24]. Nocturnal pineal melatonin peak was shown to be decreased significantly in high-fat fed rats [25]. Taken overall, these data suggest that melatonin has a strong regulatory effect on carbohydrate/lipid metabolism and BW. The exact mechanism of action is not yet fully understood but a direct effect of melatonin on adipocytes and an indirect effect via the sympathetic nervous system have both been reported [26].

Thus, melatonin has been the focus for its applicability for sleep problems and BW regulation without undesirable side effects. Melatonin has not, however, received regulatory approval from the US FDA as a drug, because it can be sold freely as a food supplement. Consequently, there has been an active search for patentable melatonin receptor ligands in recent years. NEU-P11 has been developed as a melatonin agonist with high affinity to melatonin receptors intended for the treatment of psychophysiological insomnia. In animal studies NEU-P11 demonstrates sleep promoting without deleterious effects on memory [27], [28].

The aim of this study was to investigate possible melatoninergic action of NEU-P11 on metabolism in obese rats induced by high-fat/high-sucrose diet (HFSD). We demonstrate NEU-P11 can regulate BW and improve metabolic profiles.

Section snippets

Reagents

NEU-P11 (C13H16N2O4) and melatonin (C13H16N2O2) were provided by Neurim Pharmaceuticals Ltd. (Tel-Aviv, Israel); both were dissolved in ethanol, then diluted in saline with the final ethanol concentration 0.01%. Sucrose was obtained from Liuzhou sugar Co. (Guangxi, China) and lard was obtained from Hengyang Meat Product Co. (Hunan, China).

Animals

Sixty male Sprague–Dawley rats, 2 months of age, weighed 150–200 g, were obtained from the barrier unit at the Laboratory Animal Center of Nanhua University

Effect of treatments on body and fat weight

At the first 20 weeks, i.e. before NEU-P11 or melatonin treatment, HFSD feeding resulted in a more rapid increase in BW; and at the week 0 (at this time point the treatment with NEU-P11 had not been started), HFSD rats were significantly heavier compared to the normal control group (386.00 ± 29.98 g vs. 307.00 ± 36.03 g of controls; P < 0.01) (Fig. 1A). However, supplementing NEU-P11 to those obese rats resulted in a reverse in tendency toward gaining more BW, and decreased the BW of the HFSD rats

Discussion

Studies have shown that long-term imbalance between intake and expenditure of fat is a central factor in the etiology of obesity [30]. Our current food supply is high in fat and sugar. We hypothesized that HFS diet promoted obesity by increasing energy intake, thus increasing the probability of positive energy balance and weight gain, ultimately induced obesity. In this study, all the rats were given the same amount of diet. The results show that feeding of HFS diet to rats for 5 months induced

Acknowledgments

The authors gratefully acknowledge financial support from the National Major Basic Research Program of China (973) (2006CB503808) and the National Natural Sciences Foundation of China (Projects 30370675 and 30470720).

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