Pineal melatonin secretion declines with aging, whereas visceral fat, plasma insulin, and plasma leptin tend to increase. We have previously demonstrated that daily melatonin administration at middle age suppressed male rat intraabdominal visceral fat, plasma leptin, and plasma insulin to youthful levels; the current study was designed to begin investigating mechanisms that mediate these responses. Melatonin (0.4 g/ml) or vehicle was administered in the drinking water of 10-month-old male Sprague Dawley rats (18/treatment) for 12 weeks. Half (9/treatment) were then killed, and the other half were submitted to cross-over treatment for an additional 12 weeks. Twelve weeks of melatonin treatment decreased (P Ͻ 0.05) body weight (BW; by 7% relative to controls), relative intraabdominal adiposity (by 16%), plasma leptin (by 33%), and plasma insulin (by 25%) while increasing (P Ͻ 0.05) locomotor activity (by 19%), core body temperature (by 0.5 C), and morning plasma corticosterone (by 154%), restoring each of these parameters toward more youthful levels. Food intake and total body fat were not changed by melatonin treatment. Melatonin-treated rats that were then crossed over to control treatment for a further 12 weeks gained BW, whereas control rats that were crossed to melatonin treatment lost BW, but food intake did not change in either group. Feed efficiency (grams of BW change per g cumulative food intake), a measure of metabolic function, was negative in melatonin-treated rats and positive in control rats before cross-over (P Ͻ 0.001); this relationship was reversed after cross-over (P Ͻ 0.001). Thus, melatonin treatment in middle age decreased BW, intraabdominal adiposity, plasma insulin, and plasma leptin, without altering food intake or total adiposity. These results suggest that the decrease in endogenous melatonin with aging may alter metabolism and physical activity, resulting in increased BW, visceral adiposity, and associated detrimental metabolic consequences. (Endocrinology 141: [487][488][489][490][491][492][493][494][495][496][497] 2000) T HE PINEAL GLAND secretes melatonin into the circulation almost entirely at night in vertebrates (1, 2). This nocturnal secretion mediates entrainment of endogenous circadian rhythms and influences other physiological functions. Pineal melatonin biosynthesis and secretion decline with aging; levels are significantly decreased by middle age (2, 3) and tend to decline throughout old age.Adiposity, especially visceral adiposity, increases with advancing age in humans (4), nonhuman primates (5, 6), and rats (7), as do plasma insulin and leptin levels. These changes in adiposity, insulin, and leptin levels are often associated with detrimental metabolic consequences, such as glucose intolerance, insulin resistance, diabetes, dyslipidemia, and hypertension (4,5,8). We have previously demonstrated that daily nocturnal melatonin administration to middle-aged male rats suppressed intraabdominal (commonly referred to as deep abdominal or visceral) fat, plasma leptin...
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