Adiposity, especially intra-abdominal adiposity, commonly increases by middle age in humans, non-human primates and rats, as do plasma insulin and leptin. These aging-associated increases in adiposity, insulin and leptin levels are associated with detrimental metabolic consequences, such as glucose intolerance, insulin resistance, diabetes, dyslipidemia, hypertension and cardiovascular disease. This spectrum of disorders, commonly grouped together as the """"""""metabolic syndrome,"""""""" is responsible for considerable aging-associated progressive pathology. Conversely, nocturnal pineal melatonin secretion decreases with aging in humans, other primates and rats. The proposed investigation evolves from our ongoing work demonstrating that chronic daily nocturnal administration of melatonin to middle-aged and older rats to produce youthful plasma melatonin levels and restore full amplitude circadian rhythmicity of plasma melatonin exposure also restored intra-abdominal adiposity, plasma insulin and plasma leptin to youthful levels. Administration of melatonin to young rats did not alter any of these parameters, suggesting that these responses were dependent upon the aging-associated decline in endogenous melatonin secretion. If melatonin supplementation to primates exerts these same effects, appropriate melatonin treatment could potentially provide effective prophylaxis or therapy for significant progressive pathologies associated with aging. Although indirect evidence suggests that melatonin may indeed play a role in regulating metabolism, body weight and adiposity in primates, a cause-effect relationship remains to be demonstrated. Testing this hypothesized relationship in middle-aged rhesus monkeys is the sole specific aim of the proposed investigation. A single study will be conducted, utilizing daily nocturnal intravenous melatonin vs. control infusions in unanesthetized and freely-moving middle-aged rhesus monkeys bearing indwelling vascular catheters protected by tethers. If chronic daily nocturnal melatonin treatment does decrease the monkeys' body weight, abdominal adiposity, plasma insulin, and/or insulin sensitivity to more youthful levels, the results of this investigation will justify and facilitate subsequent investigations to resolve mechanisms and clinical utility of these responses. Development of a therapy or preventive treatment that would attenuate or reverse the detrimental changes in carbohydrate and lipid metabolism which are commonly first expressed at middle age would reduce the progressive aging-associated morbidity which is the consequence of these conditions.
| Lemos, Dario R; Downs, Jodi L; Urbanski, Henryk F (2006) Twenty-four-hour rhythmic gene expression in the rhesus macaque adrenal gland. Mol Endocrinol 20:1164-76 |
| Morgan, Caurnel; Urbanski, Henryk F; Fan, Wei et al. (2003) Pheromone-induced anorexia in male Syrian hamsters. Am J Physiol Endocrinol Metab 285:E1028-38 |
