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

Abstract

Melatonin, a pineal hormone synthesized at night, is critical for the synchronization of circadian and seasonal rhythms, being a key regulator of energy metabolism in many animal species. Although studies in humans are lacking, several reports, mainly on hibernating animals, demonstrated that melatonin supplementation and a short photoperiod increase brown adipose tissue (BAT) mass. The present proof-of-concept study is the first, to our knowledge, to evaluate BAT in patients with melatonin deficiency (radiotherapy or surgical removal of pineal gland) before and after daily melatonin (3 mg) replacement for 3 months. All four studied patients presented increased BAT volume and activity measured by positron emission tomography-MRI. We also found an improvement in total cholesterol and triglyceride blood levels without significant effects on body weight, liver fat, and HDL and LDL levels. Albeit not statistically significant, fasting insulin levels and HOMA of insulin resistance decreased in all four patients. The present results show that oral melatonin replacement increases BAT volume and activity and improves blood lipid levels in patients with melatonin deficiency, suggesting that melatonin is a possible BAT activator. Future studies are warranted because hypomelatoninemia is usually present in aging and appears as a result of light-at-night exposure and/or the use of b-blocker drugs.Melatonin, a pineal hormone synthesized and released at night that plays a critical role in the synchronization of circadian and seasonal rhythms, has been studied as a key regulator of energy metabolism in many animal species for a long time (1,2). Pinealectomized rats show increased body weight gain and metabolic disturbances that are prevented by daily melatonin supplementation at night, without decreasing energy intake (1-5). This suggests that melatonin also regulates energy metabolism by its action on energy expenditure, possibly as related to the activation of brown adipose tissue (

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…Activation of brown adipose tissues leads to body weight loss, improved glucose tolerance, and decreased lipid accumulation in the liver and may be a therapeutic target for NAFLD . Halpern et al administered melatonin (3 mg) to patients with melatonin deficiency due to radiotherapy or surgical removal of pineal gland for 3 months and analyzed brown adipose tissue mass . Melatonin supplementation increased mass and activity of brown adipose tissues and decreased blood levels of total cholesterol and triglyceride .…”

“…A number of studies use various doses and administration methods (intraperitoneal injection or via drinking water), and there are no gold‐standard methods for melatonin treatments. Although a majority of current studies use 10 mg/kg/day for rats or mice, this dose may not be reasonable for human patients because melatonin tablets that can be purchased over the counter are 3 or 5 mg. Daily melatonin supplementation (3 mg) for 3 months increased brown adipose tissue mass in patients with melatonin deficiency . Although 3 or 5 mg melatonin may be effective in humans, current studies using human subjects are limited and detailed effects and optimal doses of melatonin are still undefined.…”

“…44 Melatonin supplementation increased mass and activity of brown adipose tissues and decreased blood levels of total cholesterol and triglyceride. 44 Pretreatment with melatonin (0.1-0.3 mmol/L) inhibited accumulation of cholesterol and triglyceride in hepatocellular carcinoma (HCC) line, HepG2 cells, incubated with high concentrations of oleic acid in vitro. 45 Oleic acid elevated expression levels of genes associated with de novo lipogenesis including SREBP-1c, FAS, and stearoyl-CoA desaturase 1 (SCD1) and decreased β-oxidation gene expression such as PPARα and carnitine palmitoyltransferase I (CPT1), but melatonin treatment abolished those effects leading to inhibited lipid accumulation in HepG2 cells.…”

“…Although a majority of current studies use 10 mg/kg/day for rats or mice, this dose may not be reasonable for human patients because melatonin tablets that can be purchased over the counter are 3 or 5 mg. Daily melatonin supplementation (3 mg) for 3 months increased brown adipose tissue mass in patients with melatonin deficiency. 44 Although 3 or 5 mg melatonin may be effective in humans, current studies using human subjects are limited and detailed effects and optimal doses of melatonin are still undefined. In addition, melatonin regulates circadian rhythms and melatonin secretion is rhythmic in healthy individuals, but current studies merely supplement melatonin and do not consider the timing of supplementation or rhythms.…”

Melatonin increases brown adipose tissue acute thermogenic capacity in rats measured by 18F-FDG PET

“…The images were performed around ZT 6 (six hours after lights on) to preserve the BAT peak activity in rats as described before (21) The animals received i.v. 2.474 mCi (91.54 MBq) of 18F-FDG and images were obtained by small imaging PET/CT (Triumph II trimodality System, Gamma Medica/Trifoil imaging).…”