Aging and the neuroendocrine regulation of reproduction and body weight.

Aging in men is associated with a decline in trophic factors such as testosterone (T), alterations in body composition and impaired energy and body weight regulation. We performed studies to investigate the mechanisms underlying age-related changes in the neuroendocrine control of testis function, body composition, food intake and body weight in the Brown Norway (BN) rat. We found that similar to aging men, male BN rats demonstrate both primary and secondary testicular failure with aging without confounding age-related tumors, hormonal changes and systemic illnesses. With aging, these animals have blunted circadian variations in luteinizing hormone (LH) and T, and decreased hypothalamic gonadotropin-releasing hormone (GnRH) synthetic capacity with preserved pituitary gonadotropin responses to GnRH. We found that aging male BN rats have increased peripheral and visceral adiposity associated with increased insulin and leptin levels, and decreased relative lean body mass and muscle mass. We found that these rats exhibit reduced food intake and body weight gain associated with decreased hypothalamic neuropeptide Y (NPY) gene expression in the arcuate nucleus (ARC), both during ad-libitum feeding and after a 72-h fast. Recently, we found that old male BN rats treated chronically with troglitazone, an insulin sensitizer, lowered high insulin and leptin levels, decreased body fat, and corrected the blunted food intake and body weight gain response to fasting without affecting basal ARC NPY gene expression. These findings suggested that hyperinsulinemia and/or hyperleptinemia associated with aging may contribute to the age-related impairment in energy and weight regulation. Our studies suggest that the aging male BN rat is an excellent model to investigate the mechanisms underlying the age-associated changes in the neuroendocrine control of body composition, energy intake and body weight.

Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat.

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 microg/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<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<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<0.001); this relationship was reversed after cross-over (P<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.

Cross-sectional and longitudinal analysis of age-associated changes in body composition of male Brown Norway rats: association of serum leptin levels with peripheral adiposity.

Aging-associated alterations in body composition are accompanied by changes in the endocrine system. We evaluated, in male Brown Norway rats, the effects of aging on body composition and the association with serum levels of leptin, insulin, and testosterone. Body composition was assessed cross-sectionally in male rats (3, 8, 17, and 29 months) by a combination of dual energy x-ray absorptiometry (DEXA) and dissection of specific muscles and adipose depots. Longitudinal changes in body composition were quantified by DEXA before and after 3 months of ad-libitum feeding. Body weight, lean mass, absolute and percentage fat increased with age, whereas percentage of lean mass decreased. Leptin and insulin levels increased with age in proportion to adiposity; the increase in leptin with age was related to increased total and peripheral, but not visceral, fat. Testosterone decreased with age, and was associated with decreased lean and skeletal muscle mass. These findings suggest that alterations in body composition with age may be due to decreased trophic and increased lipogenic hormones. Relative to other rodent models, Brown Norway rats undergo shifts in body composition and in the hormonal milieu that are consistent with changes seen in aging humans.

Evaluation of a rat model of valproate-induced obesity.

Long-term treatment with the anticonvulsant valproate (VPA) leads to well-documented weight gain and obesity in humans. In an attempt to develop an animal model of this condition, adult rats were given VPA 20 g/kg (high-dose) or 2 g/kg (low-dose) in their daily feeding or orally 120 mg/kg body weight/day in two divided doses, and food intake and body weight were assessed. Valproate resulted in lower body weights in all protocols. Food intake was lower (p<0.001) for rats receiving high-dose VPA than for controls. Feed efficiency (change in weight divided by cumulative food intake for that period) was lower than that of controls for both high (p<0.0001) and low doses (NS). Metabolic rate and physical activity were not different between control and VPA animals, although decreased food intake would be expected to decrease metabolic rate. Valproate failed to produce obesity in rats in any treatment period. For reasons that are unclear, rats do not appear to be suitable as a model to study this adverse side effect of VPA in humans with epilepsy.

High prevalence of gastric trichobezoars (hair balls) in Wistar-Kyoto rats fed a semi-purified diet.

Gastric trichobezoars (hair balls) are frequently found in rabbits but are rarely reported in rats. Several Wistar-Kyoto rats fed a semi-purified diet developed anorexia and abdominal tenderness. Proteolysis therapy with fresh papaya and commercially prepared enzyme was attempted in these rats but was not successful. The prevalence of trichobezoars at necropsy was 100%. We conclude that semi-purified diets contribute to trichobezoar formation in rats, but proteolysis therapy is not effective in dissolving the trichobezoars.

Insulin levels, physical activity, and urinary catecholamine excretion of obese and non-obese rhesus monkeys.

The hypothesis that spontaneous obesity in rhesus monkeys is associated with abnormalities in energy expenditure was tested. Obese (n=7) and non-obese (n=5) monkeys were described in terms of body size and composition, food intake, and physical activity. Additionally, the relationships among fasting and stimulated insulin levels in serum, C-peptide levels in serum and urine, and urinary catecholamines were examined. Obese animals had primarily abdominal deposition of excess body fat, as indicated by markedly elevated abdominal circumferences and skin-fold thicknesses. Food intake did not differ between groups. Physical activity was much lower in the obese group. Obese monkeys had markedly higher serum insulin and C-peptide levels in the fasted state and in response to an intravenous glucose challenge. Urinary excretion of C-peptide and catecholamines was measured during successive 2-day periods of ad libitum feeding, food deprivation, and refeeding in order to examine potential differences between groups in sympathoadrenal activity and their relationship to insulin secretion. C-peptide excretion was greater for obese and decreased for both groups during food deprivation. Urinary dopamine (DA), norepinephrine (NE), and epinephrine (E) levels were significantly greater for obese animals in all conditions. DA excretion was lowest during deprivation and E excretion was lowest during refeeding, whereas NE excretion was relatively unaffected by feeding condition. The overall patterns of C-peptide and catecholamine excretion were qualitatively similar for both groups, and there were no reliable differences between obese and non-obese in their responses to the feeding manipulation. The results suggest that hyperinsulinemia associated with obesity in rhesus monkeys is linked to increased catecholamine secretion and a resistance to catecholaminergic action.