Abstract:  Melatonin effect on body weight progression, mean levels and 24‐hr pattern of circulating adiponectin, leptin, insulin, glucose, triglycerides and cholesterol were examined in rats fed a normal or a high‐fat diet. In experiment 1, rats fed a normal diet were divided into two groups: receiving melatonin (25 μg/mL drinking water) or vehicle for 9 wk. In experiment 2, animals were divided into three groups: two fed with a high‐fat diet (35% fat) and melatonin (25 μg/mL) or vehicle in drinking water for 11 wk, while a third group was given a normal diet (4% fat). At the end of experiments, groups of eight rats were killed at six different time intervals throughout a 24‐ hr period. Melatonin administration for 9 wk decreased body weight gain from the 3rd wk on without affecting food intake. A significant reduction in circulating insulin, glucose and triglyceride mean levels and disrupted daily patterns of plasma adiponectin, leptin and insulin were observed after melatonin. In high fat–fed rats, melatonin attenuated body weight increase, hyperglycemia and hyperinsulinemia, as well as the increase in mean plasma adiponectin, leptin, triglycerides and cholesterol levels. The high‐fat diet disrupted normal 24‐ hr patterns of circulating adiponectin, insulin and cholesterol, the effects on insulin and cholesterol being counteracted by melatonin. Nocturnal plasma melatonin concentration in control and obese rats receiving melatonin for 11 wk attained values 21–24‐fold greater than controls. The results indicate that melatonin counteracts some of the disrupting effects of diet‐induced obesity in rats.

Male Lewis rats (6 weeks-old) were submitted to a calorie restriction equivalent to 33% or 66% of food restriction. Fifteen days later, groups of 7 animals were injected with complete Freund's adjuvant plus spinal cord homogenate (SCH) to induce experimental allergic encephalomyelitis (EAE) or with complete Freund's adjuvant alone. EAE was defined solely on clinical grounds. Rats were assessed daily for clinical signs of EAE and were killed on day 15 after immunization. Both diet and SCH injection diminished body weight significantly. In contrast to rats receiving a normal diet or a 33% calorie-restricted diet, rats subjected to severe calorie restriction did not exhibit clinical signs of EAE. Concomitantly with the lack of disease manifestation, 66% of calorie-restricted rats injected with SCH showed significantly less splenic and lymph node mitogenic response to concanavalin A (Con A) and a higher splenic response to lipopolysaccharide. Fewer splenic, lymph node and thymic CD4⁺ cells, greater numbers of splenic and lymph node CD8⁺ and CD4⁺- CD8⁺ cells, and fewer splenic T, B and T-B cells, and lymph node and thymic B and T-B cells were observed. There was impaired interferon (IFN)-γ production occurred in the three examined tissues. The results are compatible with the view that the acute phase of EAE can be curtailed by severe calorie restriction, presumably through impaired IFN-γ production.

The objective of this study was to evaluate the efficacy of melatonin to affect mild inflammation in the metabolic syndrome (MS) induced by a high‐fat diet in rats. Adult Wistar male rats were divided into four groups (n = 16/group): (i) control diet (3% fat); (ii) high‐fat (35%) diet; (iii) high‐fat diet + melatonin; and (iv) melatonin. Rats had free access to high‐fat or control chow and one of the following drinking solutions for 10 wk: (a) tap water; (b) 25 μg/mL of melatonin. Plasma interleukin (IL)‐1β, IL‐4, IL‐6, IL‐10, tumor necrosis factor (TNF)‐α, interferon (IFN)‐γ, and C‐reactive protein (CRP) were measured at two time intervals, that is, the middle of daylight period and the middle of the scotophase. In addition, a number of somatic and metabolic components employed clinically to monitor the MS were measured. Melatonin decreased the augmented circulating levels of IL‐1β, IL‐6, TNF‐α, IFN‐γ, and CRP seen in obese rats and restored the depressed levels of IL‐4 and IL‐10. Rats fed with the high‐fat diet showed significantly higher body weights and augmented systolic blood pressure from the third and fourth week onwards, respectively, melatonin effectively preventing these changes. In high‐fat‐fed rats, circulating low‐density lipoprotein‐cholesterol, total cholesterol, and triglyceride concentration augmented significantly, melatonin being effective to counteract these changes. Melatonin‐treated rats showed a decreased insulin resistance, the highest values of plasma high‐density lipoprotein‐cholesterol, and the lowest values of plasma uric acid. The results indicate that melatonin is able to normalize the altered biochemical pro‐inflammatory profile seen in rats fed with a high‐fat diet.

To examine the effect of a low dose of cadmium (Cd) as an endocrine disruptor, male Wistar rats received CdCl2 (5ppm Cd) in drinking water or drinking water alone. After 1 month, the rats were euthanized at one of six time intervals around the clock and the 24-h pattern of adenohypophysial prolactin (PRL) synthesis and release, lipid peroxidation, and redox enzyme and metallothionein (MT) gene expression was examined. Cd suppressed 24-h rhythmicity in expression of the PRL gene and in circulating PRL by increasing them at early photophase only, in correlation with an augmented pituitary lipid peroxidation and redox enzyme expression. CdCl2 treatment effectively disrupted the 24-h variation in expression of every pituitary parameter tested except for MT-3. In a second experiment the effect of melatonin (3μg/ml in drinking water) was assessed at early photophase, the time of maximal endocrine-disrupting effect of Cd. Melatonin treatment blunted the effect of Cd on PRL synthesis and release, decreased Cd-induced lipid peroxidation, and counteracted the effect of Cd on expression of most redox enzymes. A third experiment was performed to examine whether melatonin could counteract Cd-induced changes in the 24-h pattern of pituitary circadian clock gene expression and plasma PRL, luteinizing hormone (LH), thyrotropin (TSH), and corticosterone levels. Rats receiving CdCl2 exhibited a suppressed daily rhythm of Clock expression and a significant disruption in daily rhythms of pituitary Bmal1, Per1, Per2, Cry1, and Cry2. The coadministration of melatonin restored rhythmicity in Clock and Bmal1 expression but shifted the maxima in pituitary Per1, Cry1, and Cry2 expression to the scotophase. Melatonin also counteracted the effect of Cd on 24-h rhythmicity of circulating PRL, LH, TSH, and corticosterone. The results highlight the occurrence of a significant endocrine disruptor effect of a low dose of Cd. Generally melatonin counteracted the effects of Cd and ameliorated partially the circadian disruption caused by the pollutant.