Melatonin induces thermogenic gene expression in white adipose tissue (WAT) in Zucker diabetic fatty (ZDF) rats.

A Agil1, A Jiménez-Aranda1, R Ibán-Arias1, G Fernández-Vázquez0,2. 1School of Medicine (Granada), Department of Pharmacology and Neuroscience Institute, 18012, Spain, 2Carlos III Hospital (Madrid), Service of Endocrinology, 28006, Spain

Previous data from our laboratory indicate that melatonin reduces body weight gain without influencing food intake in ZDF rats, an experimental model of obesity-related type 2 diabetes and metabolic syndrome. Several lines of evidence suggest that melatonin can influence brown adipose tissue (BAT) function. Moreover, recent studies indicate that in addition to its well recognized role as triglyceride store, white fat cells can shift to brown-fat-like metabolic behaviour under the influence of certain signals, such as irisin. In order to investigate the mechanisms involved on melatonin weight control, in the present work we have studied the effects of melatonin on thermogenic gene expression in white adipose tissue (WAT) of ZDF rats. 6-week-old male ZDF rats (10 animals) were treated with oral melatonin in drinking water (10 mg/kg B.W./day) (M-ZDF) or with vehicle (V-ZDF) (control group, 10 rats). After 6 weeks of treatment (12-wk-old) animals were sacrificed and WAT was obtained. Total RNA was extracted and mRNA levels for thermogenic genes (uncoupling protein1 -UCP1-, peroxisome proliferator-activated receptor γ -PPAR γ - and PPAR γ coactivator 1α -PGC-1α-) were quantitated by real time RT-PCR using specific Taqman probes and ribosomal 18S as endogenous reference gene. mRNA levels were expressed as the mean ± SEM of arbitrary units (AU). Compared with control group, M-ZDF rats show an increase of UCP1 mRNA levels in WAT (from undetectable values to 0.50 ± 0.03; p< 0.01 ). Also, it was accompanied by a drastic increment of PPARγ mRNA levels (from 0.10 ± 0.03 to 0.80 ± 0.20; p<0.01) and of its transcriptional co-activator PGC-1α (from 0.23 ± 0.03 to 1.03 ± 0.25; p<0.01 ).

These results demonstrate that chronic oral melatonin is able to drive a brown-fat-like thermogenic gene profile to white adipose tissue. This irisin-like effect of melatonin can contribute to its capacity to body weight control, and thereby to improve obesity-related metabolic derangements such as diabetes and dyslipidemia.