1. Introduction
Even if obese individuals do not have an associated diagnosis of hypertension, type II diabetes mellitus (T2DM) or dyslipidaemia, yet there is an approximate 49% increased risk for coronary heart disease; 7% increased risk for cerebrovascular diseases and 96% increased risk for heart failure [10]. A prospective cohort study demonstrated that every kg of weight gained annually over 10 years was associated with a 49% increased risk of developing T2DM. On the other hand, every kg of weight lost annually over the same period was associated with a 33% lowered risk of developing T2DM [11].
2. Melatonin characteristics
2.1. Biosynthesis and Pharmacokinetics of exogenous supplementation
Salivary melatonin, a reliable and easily accessible biomarker, shows concentrations at around 4 pg/mL in dim-light melatonin onset (DLMO), which normally occurs between 19:30 and 22:00 in adults and between 19:00 and 21:00 in children (6 to 12 years) [28].
Exogenous melatonin, on the other hand, is shown to feature rapid absorption and plasma distribution. Its plasma concentration peaks at approximately 50 minutes after oral administration, with half-life of approximately 45 minutes [30].
Lastly, melatonin oral supplementation is metabolised in the liver by the cytochrome P450 CYP1A2 enzyme [34], where a hydroxylation reaction converts melatonin to its main metabolite 6-hydroxymelatonin sulfate, also known as 6- sulfatoxymelatonin [35, 36]. This metabolite, when measured in urine, has been used clinically as a biomarker in the fields of psychiatry [37, 38], gynaecology [22, 39] and sleep medicine [40, 41].
3. Melatonin supplementation and adipose tissue
3.1. Modulation of adipose tissue activity
It has been demonstrated in rats that melatonin appears to induce lipolysis [55,56], which is further corroborated by findings of reduced lipolysis and increased lipogenesis in pinealectomized rats [57]. Mechanistically, melatonin administration not only reduces total body fat, but more specifically intra-abdominal, retroperitoneal, hepatic and visceral fat in experimental models [58]. The lipolytic mechanisms modulated by melatonin are illustrated in Figure 1.
A recent study employing diet-induced obese rats found that the time of the day in which melatonin was administered had an impact on BAT metabolism, being more effective late in the evening as compared to morning administration [64].
3.2. Body composition: weight and fat loss
The effects of melatonin supplementation as modulator of body composition have been previously discussed in previous studies [72-74]. In a doubleblind randomised clinical trial (RCT), Amstrup et al [75] reported that a group of postmenopausal eutrophic women diagnosed with osteopenia and treated with melatonin (1 and 3 mg/day) for 12 months showed improved body composition, measured by dual X-ray absorptiometry, as compared to the women who received placebo [75]. The researchers also found at the end of the 12 months study a 6.9% reduction in fat mass combined with a 5.2% increase in lean mass in the melatonin receiving group.
In an investigation associating melatonin supplementation (10 mg/day 1 h before bedtime) combined with calorie-restricted diet (1,000–1,200 kcal/d for women and 1,400–1,600 kcal/d for men) in adult patients with obesity, the intervention with melatonin was able to enhance weight loss further, from 113.6 to 105.9 kg, as compared to the placebo-receiving group, from 114.4 to 109.8 kg. Additionally, malondialdehyde (MDA) levels, an oxidative stress biomarker, had greater reduction in the melatonin group, from 34.3 to 24.5 nmol/g Hb, when compared to placebo, from 30.1 to 27.4 nmol/g Hb [76].
Walecka-Kapica et al [80] found a significant reduction in body mass index (BMI) in postmenopausal women (mean age 56.9 ± 5.3) with high (from 29.62 to 27.88 kg/m²; p<0.001) and normal (from 22.07 to 21.86 kg/m²; p<0.05) body weight under combined therapy of melatonin supplementation (5 mg/day for 24 weeks) and a balanced diet of 1,500 kcal/d.
In another study involving postmenopausal overweight women, melatonin supplementation at a dosage of 5 mg/day associated with fluoxetine at 20 mg/day for 24 weeks resulted in improved sleep quality, in addition to reduced appetite and BMI, from 30.9 to 26.3 kg/m² [82].
In the opposite direction to what has so far been discussed in this section, other studies have shown that melatonin supplementation have not ameliorated body composition in obese women [86], neither in diabetic [87] nor in metabolic syndrome [88] patients.
Two recent meta-analyses have appraised clinical trials focusing on body composition and melatonin supplementation. In the meta-analysis of Mostafavi and colleagues published in 2017 [89], which covered seven clinical trials and a total of 244 participants based on Mostafavi’s inclusion criteria, melatonin supplementation alone was ineffective in inducing weight loss, but showed a positive effect when combined with other strategies. A more recent meta-analysis, published in 2019, showed that melatonin supplementation alone improved selected lipid biomarkers but was ineffective in inducing weight loss [90]. Such result was found based on their inclusion criteria, which selected 12 trials, from whom a subset of 6 trials was examined for effects on weight loss, covering a population of 338 individuals. The authors themselves recognised a few limitations in their selection of clinical trials, such as low sample size, lack of clarity in the blinding process of the studies appraised and selection of their participants, as well as heterogeneity attributed to the differences in characteristics, including range of diseases, amongst the selected studies.
4. Musculoskeletal metabolism and lean body mass
The adipose tissue and skeletal muscle are the two largest insulin-responsive tissues in the human body, and responsible for the secretion of adipokines and myokines, respectively [91]. Both families of bioactive molecules act in synergy to regulate a vast range of biochemical pathways involved in energy metabolism and lipid storage, and it is widely accepted that disturbances in the lean/fat mass ratio lead to several metabolic diseases. Muscle mass is protective against not only obesity but also other metabolic disturbances, including sarcopenic obesity [92], which is characterized by impaired function and strength of skeletal muscle [93].
5. Cardiovascular and lipid profile outcomes
A few review papers have reappraised the effects of melatonin supplementation in the field of cardiology [101-103]. As an adjuvant antihypertensive agent, melatonin has been proposed as a modulator of oxidative stress at vascular endothelium level [104]. In a small population of healthy volunteers, the acute effects of a single 3 mg dose of melatonin were tested. As a result, forearm blood flow and vascular conductance were increased 45 minutes after its ingestion, as compared to the same individuals taking placebo a few days later [105]. Such effects may be explained by activation of MT2 receptors and subsequent vasodilation of the capillary bed [47, 106].
6. Biochemical modulation of hepatic parameters
Correspondingly, a recent meta-analysis of RCTs reported appealing results of melatonin supplementation on the traditional clinical panel used in the management of liver diseases, such as a reduction in gamma-glutamyl transferase (GGT) (-33 IU/L) and alkaline phosphatase (ALP) (-8 IU/L) levels [118].
7. Glucose homeostasis and insulin sensitivity
Melatonin is known to participate in the intracellular processes that regulate insulin secretion and blood glucose homeostasis by its binding to MT1 and MT2 receptors in the pancreatic beta cell [120, 121].
8. Mitochondrial modulation: oxidative stress and antioxidant potential
9. Therapy of obesity: open questions about melatonin supplementation as a possible tool
Historically and still currently, several pharmacological agents have been employed for the management and or treatment of obesity. For example, Franz et al [143] in their meta-analysis found an average of 5% to 9% weight loss during the first 6 months of interventions based on low calorie diets, combined or not with orlistat or sibutramine, but the weight losses observed tended to plateau after 6 months, and in several instances were not maintained.
10. Safety of supplementation
Firstly, upon analyses of experimental models, hyper doses of melatonin showed no signs of toxicity and lethality [146, 147]. Such safety has also been demonstrated in pregnant rats, demonstrating an absence of toxicity for both the mother and the foetus in doses up to 200 mg/kg/day [148]. In humans, several studies have deemed melatonin supplementation to be safe, and no dramatic side effects or toxicological issues have been reported within the dosages investigated [149-151]. Melatonin supplementation at a dosage of 50 mg/day—a dose considered high—for 2 weeks to elderly patients suffering with Parkinson's disease was deemed to be safe, with 2 out of 40 subjects reporting daytime tiredness as a side effect [20]. A meta-analysis of 8 RCT supplementing 20 mg/day of melatonin to cancer patients showed no significant side effects attributed to melatonin [152].
Referência :
(1) Pharmacol Res. 2021 Jan;163:105254.
