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Treatments of human and rodent obesity frequently involve administration of amphetamine derivatives, much like phenylpropanolamine, which suppress food intake. The Zucker rat is a commonly employed model of youth-onset obesity in which the homozygous genotype manifests hyperphagia as well as other characteristics that parallel human obesity. Using a macronutrient selection procedure, we examined phenylpropanolamine's differential actions in controlling dietary intake, spontaneous open-field activity, and regional hypothalamic neurotransmitter levels in obese female Zucker rats of varying fat food preference. We hypothesized that phenylpropanolamine would alter hypothalamic monoamine levels differently in low-fat preferring and high-fat preferring Zucker rats, and hence affect feeding behavior and activity differently in these two groups. It was found that in high-fat preferring animals, phenylpropanolamine significantly decreased spontaneous open-field activity, decreased only carbohydrate caloric intake, and increased serotonin and 5-HIAA levels in the paraventricular nucleus (PVN). In low-fat preferring animals, phenylpropanolamine decreased carbohydrate, protein, and total caloric intake, had no significant effect of spontaneous activity, and increased serotonin and 5-hydroxyindole acetic acid levels in the PVN. Inherent and induced physiological differences of low-fat and high-fat preferring animals are discussed as well as phenylpropanolamine's potential in combination drug therapy for the treatment of human hyperphagic obesity. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated that neuropeptide Y (NPY) reduced the neural production of dehydroepiandrosterone (DHEA) in frog hypothalamic explants. The objective of this study was to assess if DHEA can block the NPY induced increase in food intake in lean and obese Zucker rats. Rats were given one of the following four treatments: sterile water/dimethylsulfoxide (DMSO), NPY/DMSO, water/DHEA, and NPY/DHEA. Immediately after administration of their respective treatment, rats were exposed to macronutrients for 4 h and food intake was monitored. NPY caused a significant increase in total calories consumed compared to control. Co-administration of DHEA along with NPY blocked this NPY dependent effect. These results suggest that DHEA blocks the over-eating in satiated rats induced by NPY. Measurement of changes in regional hypothalamic and raphe monoamine neurotransmitters known to affect food intake suggested a possible role of serotonin fluctuations in the ventromedial hypothalamus (VMH) guiding this behaviour.

Zucker rats, lean and obese, treated with low dose intraperitoneal injections of streptozocin become hyperglycemic within 24h. Insulin levels fall, although the obese animal remains hyperinsulinemic. Associated with these changes in glucose and insulin there are transient decreases in caloric intake. Macronutrient selection studies show that protein consumption decreases. There is a trend for fat intake to decrease. The levels of hypothalamic neurotransmitters in the lean animals are not altered by streptozocin. The levels of 5-hydroxyindoleacetic acid increases in the streptozocin-treated obese animal in the paraventricular region, ventromedial region and the raphe. Serotonin is also significantly increased in the paraventricular region of the obese rat. These results suggest that acutely, treatment with streptozocin injures pancreatic islets, causing, in turn, decreases in insulin levels so that hyperglycemia ensues in both phenotypes. Associated with these perturbations are decreases in caloric intake. The magnitude of change in insulin levels is much greater in the obese rat. It is hypothesized that in the obese Zucker rat decrements in food intake are mediated by increase in serotonin turnover in the hypothalamus and these changes are related to changes of insulin levels. These data support the concept that circulating insulin affects hypothalamic neurotransmitters.

Hypothalamic neurotransmitter levels were compared between groups of Zucker rats. Animals were grouped by gender, phenotype and preference for dietary fat. Before sacrifice all animals consumed a standard rat chow diet and were fasted overnight. Five rats from each of eight groups were assayed. Hypothalamic regions (lateral, LH; ventromedial, VMH; paraventricular, PVN) and the raphe were isolated and analyzed for dopamine, norepinephrine, epinephrine, serotonin and 5-hydroxyindoleacetic acid. A factorial analysis of variance was used to compare the concentrations of these biogenic amines in the four regions across phenotypic, gender and fat preference profiles. No differences were demonstrated between groups based upon fat food preference. Epinephrine and 5-HIAA content varied between lean and obese animals but there were no differences in the content of serotonin, norepinephrine or dopamine. The results are consistent with the hypothesis that the obese animal eats more because it releases less of the satiety-inducing neurotransmitter serotonin in the hypothalamus.

Cyclo (His-Pro) (CHP) is a gut-brain peptide whose plasma levels in humans are increased after glucose ingestion and preferentially altered by oral glucose ingestion compared to intravenous administration in rats, suggesting a role in the enteroinsular response to nutrient ingestion. We were interested in examining levels of CHP in women of differing weights and comparing these levels to various parameters of insulin secretion. Plasma from 26 fasting, nondiabetic women ranging from 21 to 70 years of age and weighing 43 to 114 kg was assayed for CHP. Insulin and C-peptide levels were measured in 17 of the 26. Fasting CHP levels were elevated in obese compared to nonobese women (2075+/-144 vs. 905+/-187 pg/ml; p < 0.001) and were related by regression analysis to weight (r = 0.668, p < 0.001) and body mass index (r = 0.636, p = 0.001). The fasting C peptide/insulin molar ratio, which may be used as an estimate of hepatic insulin clearance (HIC), was inversely related to CHP levels (r = -0.568, p = 0.017). We conclude CHP levels are increased in obese women and inversely related to their C-peptide/insulin molar ratio. The elevation of CHP in those with a decrease in this estimate of HIC (obese) is interesting as the greater insulin response seen in normal persons after oral glucose compared to intravenous glucose has been postulated to be due to a decrease in HIC by some gut factor. The presence of such a factor in excess in the obese might explain part of their hyperinsulinemia.

Food intake is controlled by hypothalamic neurotransmitters. Exogenous dehydroepiandrosterone (DHEA) decreases Zucker rat caloric intake, alters selection of macronutrients and affects the level of hypothalamic neurotransmitters. The goal of this study was to determine whether the changes induced by the administration of DHEA on hypothalamic neurotransmitters depend on the diet the animals are consuming. Groups of obese, female Zucker rats were fed one of four separate diets: One contained all three macronutrients (fat, carbohydrate and protein). The others consisted of single macronutrients only. Two days later, the animals were treated with 200 mg DHEA/kg body weight (or vehicle only) and then sacrificed the next day. Three hypothalamic regions (the lateral hypothalamic, the ventromedial hypothalamic and paraventricular hypothalamic) were isolated and their content of norepinephrine, epinephrine, dopamine, serotonin and 5-hydroxyindole acetic acid determined. DHEA changed the levels of neurotransmitters compared to untreated controls with the specific changes depending upon the diet the animal had been consuming. In conclusion, DHEA affects both the catecholamine and the serotonin systems, however, diet influences the specific neurochemical changes.

Because of changes wrought by the U.S. Dietary Supplement Health and Education Act of 1994, DHEA (dehydroepiandrosterone) is now available to the general population as a dietary supplement. Although advertising of any health benefit is restricted, many people take it for purported salutary effects of age-related processes. One of these suspected benefits is the delay of Alzheimer's disease. This review evaluates the literature derived from both animal and human trials that leads people to believe DHEA may exert such an effect. It will show that DHEA is active in the central nervous system when given exogenously, is made in the central nervous system of laboratory animals and may have a role in regulating normal physiologic processes. Possible cellular mechanisms of action are described. DHEA may have particular effects on learning and memory in test animals, but there is only sparse data in humans where observations are indirect and poorly controlled. Still, it is concluded that the data is compelling enough to warrant further research, although it is premature to suggest a safe dosing schedule for humans who may want to try this steroid hormone.

Lean and obese Zucker rats were deprived of food for 12, 24, and 48 h. After sacrifice, plasma and brain tissue were saved for hormone and regional hypothalamic monoamine analysis. An ad libitum group was killed at time 0 for comparison to the food deprived groups. Insulin (I), C-peptide (CP), glucose, and the CP/I ratio were dramatically different across phenotype. Glucagon was only different at 12 h of caloric deprivation. Insulin secretion dropped substantially with fasting as reflected by the decrease in C-peptide plasma levels in both lean and obese rats. The CP/I ratio, which indicates clearance of insulin, increased in lean rats across time of fasting but did not significantly change in obese rats. Several distinct changes occurred between phenotypes in the hypothalamus across food deprivation. Lateral hypothalamic 5HT content and 5HT turnover (5HIAA/5HT) increased in lean but not obese rats during the period of fasting. Likewise ventromedial hypothalamic dopamine turnover (NE/DA) decreased during caloric deprivation in lean rats but not in the obese rats. This same turnover was increased in the PVNA of obese but not lean rats during caloric deprivation. Individual measurements of both C-peptide and insulin correlated significantly with LH 5HT turnover and VMH dopamine turnover in lean rats but not obese rats. These data suggest that obese rat's hypothalami may possibly be insensitive to insulin or some factor such as leptin that insulin may regulate. Because obese rats cannot change their levels of hypothalamic neurotransmitters when insulin or some other insulin induced factor changes, may suggest clues as to why these rats became obese. Perhaps these data may help explain the altered body weight set-point, increased adiposity, and hyperphagia in these animals.

Treatment with dehydroepiandrosterone (DHEA) leads to a decrease in the fat stores of a variety of rodent models of obesity. However, whether DHEA affects food intake and whether such changes are important at reducing obesity is not settled. Some state that food intake is not altered by DHEA and that the effect on weight gain is caused by induced inefficiencies in metabolism. Others report that DHEA leads to a prompt decrease in caloric consumption and that this change is important in causing weight loss. In this commentary the data supporting both sides of this controversy are reviewed. Analysis suggests that these radically different conclusions are caused by investigators using studies of different experimental design; shorter experiments emphasize DHEA's effects on food intake, while longer experiments tend to emphasize DHEA's metabolic effects. In addition the way the investigators normalize their food intake results for differences in animal size may influence their analyses. It is concluded that DHEA exerts both a metabolic effect and an effect on caloric intake and that both are involved in medicating changes in fat stores of obese animals.