Melatonin Increases Brown Adipose Tissue Volume and Activity in Patients With Melatonin Deficiency: A Proof-of-Concept Study

Discussion

The present study shows a significant increase in BAT volume and activity after melatonin replacement therapy as measured by PET-MRI in four patients with melatonin deficiency as a result of pinealectomy. Despite the very small sample size, the increase was observed in all patients, suggesting that melatonin may be a potential BAT recruiter that should be taken into consideration in further studies in humans, at least in situations in which a reduction in melatonin production occurs. Many experimental studies associated melatonin treatment with an increase in BAT mass as well as melatonin deficiency with a decrease in BAT mass, but these data were restricted to animal studies, mainly hibernating animals (3), and were obtained before the identification of active BAT in human adults (6–8). Today, BAT is being studied in view of its possible relation with obesity, type 2 diabetes, and other metabolic diseases, and potential BAT activators and recruiters have been proposed (20) as adjuvant treatment of these diseases. Some authors hypothesized that an increase in BAT not only would lead to increased energy expenditure after cold exposure but also could be related to diet-induced thermogenesis (21,22).

The present observed increase in volume suggests that melatonin replacement is able to recruit BAT, with a greater activation in response to the acute cold challenge. Melatonin replacement to pinealectomized animals decreases body weight gain with a very small decrease in food intake, with the increased energy expenditure being the most plausible mechanism for the final body weight reduction (5). Taking these experimental data and the present results into account, it is possible to speculate that the same may be true in humans (1), even though energy expenditure was not addressed.

Because several clinical and social conditions that present hypomelatoninemia, such as LAN, diabetes, and neurological disorders (2), are associated with increased body fat, a reduction in BAT as a result of the hypomelatoninemic condition could be a possible explanation for this correlation (23), but we do not have any direct evidence of that. Importantly, we do not believe that melatonin could be an independent antiobesity drug, but rather, a deficiency in melatonin could lead to weight gain in the long-term (5), and its replacement or supplementation could prevent weight gain in some obesogenic situations, such as reduced BAT activity after the use of antipsychotic drugs (13,14).

It is interesting to note that patient 2 had a high BAT activity even before melatonin replacement, suggesting that BAT recruitment and/or activation can occur in the absence of melatonin. However, the further increase in activity after replacement in this patient suggests an important role played by melatonin even when BAT is already reasonably recruited.

The observed reduction in triglyceride and total cholesterol levels is in agreement with the conclusion of a recent meta-analysis (15). However, none of the studies included in the meta-analysis evaluated patients with melatonin deficiency, and the present results with such a small sample suggest that the clinical benefit to lipid levels would be much higher in patients with melatonin deficiency. Such a suggested positive correlation between the therapeutic effect of melatonin and the previous endogenous amount of melatonin production was already demonstrated in sleep and daily activity/rest rhythm clinical studies (24). Notably, two of our four patients had an increase in HDL cholesterol of ∼10 mg/dL, with clinical significance. Differently from other studies, liver fat evaluated by MRI was not affected by melatonin supplementation (25,26). Although no difference was observed in the glycemic parameters (which is somehow expected because of the small number of patients), fasting insulin and HOMA-IR were reduced in all four patients after melatonin replacement (despite the weight gain in three of them), with a clinically significant reduction in patients 1 and 4 (Table 1). In our opinion, it is possible to speculate that a reduction in IR could likely be observed in a larger sample and can possibly be related to an increase in BAT activity and recruitment after melatonin treatment because BAT activation is known to improve whole-body glucose homeostasis in humans (18).

This small pilot study is innovative for several reasons. It is the first study in our knowledge to objectively analyze BAT activity after melatonin treatment in humans, despite a huge amount of data in animals. Although the clinical significance of this finding cannot be clearly defined (since energy expenditure was not addressed, the sample is small and the duration is shorter than required to evaluate body weight or glycemic responses), melatonin and its agonists could be considered potential BAT-recruiting agents for future research. Moreover, we studied patients with melatonin deficiency as a result of pinealectomy, individuals who have received very little attention in the previous literature. There is virtually no study (with the exception of a few individual case reports) that evaluated melatonin replacement in these patients (27). Since melatonin is a known chronobiotic in humans (2), we strongly expect that its replacement therapy could improve sleep and quality of life of our present patients. Many decades of research in pinealectomized animals have shown important metabolic derangements, such as weight gain, IR, and decreased thermoregulatory responses, as well as remarkable effects of melatonin replacement in reversing these alterations (1,2). However, no data are available in humans that evaluated either the baseline metabolic characteristics of patients who had undergone pinealectomy or the effects of melatonin replacement therapy. Besides that, we decided to study patients with pinealectomy to mirror the evidence obtained in animal models, in which the metabolic effect of melatonin replacement is clearly evident. The positive results of the present small study warrant a placebo-controlled study to evaluate sleep, cardiovascular disease, and energy metabolism in a larger sample of patients with melatonin deficiency, potentially indicating a systematic melatonin replacement treatment of those patients in the future. In addition, once the putative therapeutic effects of melatonin are shown in this melatonin-deficient population, future studies should also look at several clinical and social situations leading to the so-called hypomelatoninemia condition (2), such as shift work, excessive LAN exposure, β-blocker use, neurologic disorders, and aging (28–30). All these conditions are associated with weight gain and metabolic diseases, and it remains to be determined whether melatonin supplementation has an impact on body weight and metabolic parameters also in these patients. We decided not to study control subjects since they are regular producers of melatonin, and the use of melatonin for 3 months in healthy individuals could have low adherence because of putative side effects, such as headache, drowsiness, or daytime somnolence (31).

In conclusion, in this small sample of patients who had undergone pinealectomy with confirmed very low melatonin levels, replacement with 3 mg of melatonin increased BAT volume and activity analyzed by PET-MRI as well as reduced total cholesterol and triglyceride levels. Melatonin could be considered a possible BAT recruitment agent in humans with the potential for future therapeutic use. Further research on melatonin supplementation in a larger sample of patients with pinealectomy and other clinical situations associated with melatonin reduction is warranted since the paucity of data in the literature is evident.