A recent USA national survey showed that patients with MetS were found to have a low serum antioxidant capacity compared with those without MetS (Beydoun et al. 2011). Therefore, along with other substantial interventions (e.g. sustained lifestyle modification with calorie restriction, increased physical activity and adjuvant drugs), antioxidant supplementation in the management of the MetS or prevention of increased oxidative stress associated with obesity-related alterations is currently receiving much attention.
The pineal gland hormone melatonin has potent antioxidant activities (Korkmaz et al. 2009a). In addition, it has been shown to play a role in metabolic regulation (Korkmaz et al. 2009b, Tan et al. 2011). Convincing evidence exists for the association of circadian system derangement (chronodisruption), sleep deprivation and melatonin suppression in MetS and obesity (Reiter et al. 2011).
Melatonin: a multifunctional molecule more than an antioxidant
Melatonin or N-acetyl-5-methoxytryptamine is the hormone secreted mainly by the pineal gland that is under the control of the central nervous system via the suprachiasmatic nucleus (SCN) of the hypothalamus. Because the pineal gland is active only in darkness, the levels of melatonin in the pineal gland and in blood are high at night and low during the day (Altun et al. 2002). The biosynthesis and metabolism of melatonin have recently been extensively reviewed (PandiPerumal et al. 2006, Hardeland 2008).
Viewed as nature’s most versatile biological signalling (Pandi-Perumal et al. 2006) and multitasking molecule (Reiter et al. 2010a), melatonin is a highly conserved molecule found in almost all groups of organisms (Hardeland & Fuhrberg 1996). Beside its classical role as a chronobiotic factor or endogenous synchronizer participating in the regulation of seasonal as well as circadian rhythm (Zawilska et al. 2009), melatonin is also involved in a wide range of physiological functions in humans and animals having anti-excitatory, antioxidant, anti-inflammatory, immunomodulatory and vasomotor effects (for review see Hardeland et al.(2006), Pandi-Perumal et al.(2006)). Many of the biological actions of melatonin are elicited through the activation of membrane (Hardeland et al.2006, Pandi-Perumal et al.2008) or nuclear (Wiesenberg et al. 1998, Carlberg 2000) receptors while some of its intracellular actions are receptor-independent (for example, free radical scavenging). Two types of membrane receptors have been identified in mammals: melatonin receptor type 1 (MT1 in rodents or MTNR1A in humans) and type 2 (MT2 in rodents or MTNR1B in humans); they belong to the family of G-protein-coupled receptors (for review see Hardeland et al. (2011)) and are increased in patients with type 2 diabetes (Peschke et al. 2007).
The antioxidant activity of melatonin is well established (for reviews see Tan et al. (2007), Korkmaz et al. (2009a)). Most of the studies used melatonin at very high concentrations (1 lM–100 mM) compared to its physiological concentrations (10–60 and 43– 400 pM during the day and the night respectively) (Barrenetxe et al. 2004, Bonnefont-Rousselot & Collin 2010). In both in vitro and in vivo experiments, melatonin administration was able to neutralize a number of toxic reactants including reactive oxygen species (ROS) and free radicals [(Reiter et al. 2000, 2008) and no toxicity was found when melatonin was administered to experimental animals or humans at doses varying between 1 and 300 mg per day (Bonnefont-Rousselot & Collin 2010)]. It has also been shown to increase the expression and activity of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (Vural et al. 2001, Rodriguez et al. 2004) and to increase the efficacy of classic antioxidants such as vitamin E, vitamin C and glutathione (GSH) (Gitto et al. 2001). Furthermore, several melatonin metabolites [e.g. N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK)] which are formed when melatonin neutralizes damaging reactants are themselves free radical scavengers (Tan et al. 2007, Reiter et al. 2008). This would increase the efficacy of melatonin in pathological conditions associated with increased oxidative stress (Korkmaz et al. 2009a, Bonnefont-Rousselot & Collin 2010).
Melatonin is a small, highly lipophilic and hydrophilic molecule able to cross all morphological barriers and acts not only in every cell but also within every subcellular compartment (Vural et al. 2001, Rodriguez et al. 2004).
Cardiovascular effects of melatonina
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Melatonin and obesity
Melatonin is involved in energy expenditure and body fat mass regulation (Korkmaz et al. 2009b, Tan et al. 2011). Previously reported in seasonal animals (Bartness & Wade 1985), the role of melatonin in body weight regulation was clearly demonstrated by the observation that the reduction in circulating melatonin in pinealectomized rats was followed by an increase in body weight and that intraperitoneal (ip) administration of melatonin (30 mg kg1 day1 for 3 weeks) to these pinealectomized animals reversed the body weight gain (Prunet-Marcassus et al. 2003).
It was shown that the amplitude of the nocturnal pineal (Cano et al. 2008) and serum (Peschke et al. 2006) melatonin peaks decrease significantly in obese animals. Daily melatonin supplementation (4–10 mg kg1 for 8– 12 weeks) significantly reduced body weight as well as plasma glucose, leptin, triglyceride (TG) and total cholesterol levels of the rat models of high-fat dietinduced obesity (Prunet-Marcassus et al. 2003, She et al. 2009, Rios-Lugo et al. 2010).
Despite the studies on the antioxidant activities of melatonin in experimental obese animals, only few have been performed in obese humans. In a recent promising study carried out by Kozirog et al. (2011), 1 month of administration of melatonin (5 mg day1) to patients with MetS reduced the body mass index (BMI), SBP and plasma fibrinogen as well as thiobarbituric acid-reactive substrates (TBARS) levels. Interestingly, after 2 months of treatment, there was a further significant improvement in SBP and antioxidative status as indicated by an elevated catalase activity and a decrease in low-density lipoprotein cholesterol (LDL-C) levels (Kozirog et al. 2011). Although no information was given about the levels of circulating melatonin and insulin, this report pointed out, as claimed by other authors, that the levels of melatonin per se are not as important as the melatonin/insulin ratio that correlates negatively with the lipid profile of patients with MetS (Robeva et al. 2008).
Melatonin has been implicated in the regulation of insulin secretion and glucose/lipid metabolism (Nishida 2005, Peschke 2008, Peschke & Muhlbauer 2010). Studies on pinealectomized animals also gave more insight into the role of melatonin in insulin resistance: in normal rats, pinealectomy induced insulin resistance and glucose intolerance (Lima et al. 1998, Zanquetta et al. 2003). In type 2 diabetic rats, pinealectomy increased plasma insulin significantly (after 21 weeks) and caused accumulation of TGs, which was followed later (after 35 weeks) by a net decrease in insulin levels (Nishida et al. 2003), reflecting impairment in insulin release from pancreatic b-cells, as seen in patients at an advanced stage of type 2 diabetes mellitus (Kuzuya et al. 2002). Pineal gland melatonin synthesis is decreased in type 2 diabetic Goto-Kakizaki rats (Frese et al. 2009); long-term melatonin consumption (2.5 mg kg1 day1 for 9 weeks) increased plasma melatonin levels with a concomitant reduction in insulin levels in these animals (Peschke et al. 2010). Melatonin (1 nM) treatment has been shown to stimulate glucose transport in skeletal muscle via the phosphorylation and activation of IRS-I and PI-3K respectively (Ha et al. 2006). It was further demonstrated that melatonin improves glucose homeostasis by restoring the vascular actions of insulin, which were characterized by increased phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) in aortic tissue (Sartori et al. 2009). In addition to the above, melatonin receptors, MT1 and MT2 are also expressed in pancreatic islets (Peschke et al. 2000) and as insulin levels exhibit a nocturnal drop, its production has been suggested to be controlled, at least in part, by melatonin (Mulder et al. 2009).
Melatonin and leptin resistance
Pinealectomy increases circulating leptin (Baydas et al. 2001), while exogenous melatonin decreases serum leptin levels in both pinealectomized (Canpolat et al. 2001) and intact rat models of diet-induced obesity (WoldenHanson et al. 2000) before decreasing plasma insulin levels (Puchalski et al. 2003).
At a molecular level, the mechanisms of leptin resistance and impaired leptin signalling include amongst other things increased the activity of suppressor of cytokine signalling 3 (SOCS3) (Bjorbaek et al. 1999, Emilsson et al. 1999), which is a member of a family of proteins, which inhibits the JAK-STAT signalling cascade (Myers et al. 2008). Melatonin may act initially on hypothalamic leptin and insulin receptor sensitivity (as these hormones do under normal conditions) and may consequently relay information about peripheral fat stores to central effectors in the hypothalamus to modify food intake and energy expenditure (Song & Bartness 2001).
Referência :
Acta Physiol (Oxf). 2012 Jun;205(2):209-23.
