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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.

The 5 HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetraline (8-OH-DPAT) increases the food intake of satiated Zucker rats, both lean and obese. Associated with this increased intake are changes in the hypothalamic content of serotonin and its metabolite, 5-HIAA (5-hydroxyindole-3-acetic acid); serotonin is increased while the level of 5-HIAA is decreased. Analysis of individual 5-HIAA/5-hydroxytryptamine (5-HT) ratios, a measure of serotonin turnover indicate that 8-OH DPAT affected serotonin turnover equally and dramatically in both phenotypes. This would be an expected physiological action of an autofeedback mechanism by a 5-HT(1A) receptor agonist. Dehydroepiandrosterone (DHEA) at doses as low as 10 mg/kg blocks the 8-OH-DPAT-induced increase in food intake but does not alter food intake of control satiated Zucker rats. The mechanism of DHEA's action was investigated by monitoring the steroid's effect on hypothalamic neurotransmitters in this satiated model. DHEA by itself induced some change in 5-HIAA in the obese satiated model but not the lean. 8-OH-DPAT, by itself, dramatically decreased serotonin turnover in either lean or obese rats, and DHEA combined with 8-OH-DPAT did not further change serotonin turnover, suggesting DHEA may work through mechanisms other than monoamines to cause its inhibition of 8-OH-DPAT-induced behavioral effects at such low doses.

Insulin-resistant muscle tissue contains low proportions of arachidonic acid (AA), and increased proportions of muscle AA correlate with improved insulin sensitivity. Dehydroepiandrosterone (DHEA) and AA, like the thiazolidinedione drugs that decrease insulin resistance (IR), are peroxisome proliferators. Long-chain fatty acids (FA) have been named the "one true" endogenous ligand for activating the peroxisome proliferator-activator receptor (PPAR), and DHEA has been named a "good candidate" as a naturally occurring indirect activator of PPAR. This study was conducted to determine DHEA's effects on lipid profiles of skeletal and cardiac muscle in lean and obese Zucker rats (ZR), a model of IR, type 2 diabetes mellitus, and obesity. We hypothesize that DHEA may alter long-chain FA profiles in muscle tissue of obese rats such that they more closely resemble that of the lean. In our experiments, we employed a DHEA and a pair-fed (PF) group (n = 6) for 12 lean and 12 obese ZR. For 30 d, the diet of the two DHEA groups was supplemented with 0.6% DHEA; PF groups were given the average daily calories consumed by their corresponding treatment group. Hearts and gastrocnemius muscles were assayed for phospholipid (PL), free FA, and triglyceride (TG) FA profiles. The proportion of PL AA was significantly greater in both muscle types of lean compared to obese rats. Hearts from both DHEA groups had greater PL proportions of AA and less oleic (18:1) acid than their PF controls. Likewise, 18:1 proportions were significantly lower in the gastrocnemius; however, AA proportions were not significantly different. Similar phenotypic profile differences were observed in the TG fraction of both muscle types. There were no DHEA-related TG FA profile alterations.

High levels of serum free fatty acids (FFA) and lower proportions of polyunsaturated (PU) FAs, specifically arachidonic acid (AA), are common in obesity, insulin resistance (IR), and type 2 diabetes mellitus. Dehydrepiandrosterone (DHEA) decreases body fat content, dietary fat consumption, and insulin levels in obese Zucker rats (ZR), a genetic model of human youth onset obesity and type 2 diabetes. This study was conducted to investigate DHEA's effects on lean and obese ZR serum FFA levels and total lipid (TL) FA profiles in heart and soleus muscle. We postulated that DHEA alters serum FFA levels and tissue TL FA profiles of obese ZR so that they resemble the levels and profiles of lean ZR. If so, DHEA may directly or indirectly alter tissue lipids, FFA flux, and perhaps lower IR in obese ZR. Lean and obese male ZR were divided into six groups with 10 animals in each: obese ad libitum control, obese pair-fed, obese DHEA, lean ad libitum control, lean pair-fed, and lean DHEA. All animals had ad libitum access to a diet whose calories were 50% fat, 30% carbohydrate, and 20% protein. Only the diets of the DHEA treatment groups were supplemented with 0.6% DHEA. Pair-fed groups were given the average number of calories per day consumed by their corresponding DHEA group, and ad libitum groups had 24-h access to the DHEA-free diet. Serum FFA levels and heart and soleus TL FA profiles were measured. Serum FFA levels were higher in obese (approximately 1 mmol/L) compared to lean (approximately 0.6 mmol/L) ZR, regardless of group. In hearts, monounsaturated (MU) FA were greater and PU FA were proportionally lower in obese compared to the lean rats. In soleus, saturated and MU FA were greater and PU FA were proportionally lower in the obese compared to the lean rats. DHEA groups displayed significantly increased proportions of TL AA and decreased oleic acid in both muscle types. Mechanisms by which DHEA alters TL FA profiles are a reflection of changes occurring within specific lipid fractions such as FFA, phospholipid, and triglyceride. This study provides initial insights into DHEA's lipid altering effects.

Background: The obese Zucker rat exhibits insulin resistance, develops nephropathy at an early age, and may be a model of diabetic nephropathy. Dehydroepiandrosterone (DHEA) may ameliorate many of the factors that contribute to diabetic nephropathy, while angiotensin-converting enzyme inhibitors are known to be effective. One marker of nephropathy is the expression of alpha-smooth muscle actin., Methods: We studied the effect of DHEA on the expression of alpha-smooth muscle actin in obese Zucker rats and compared the changes with those in a control group, a group given quinapril, and a group on a low-calorie diet. DHEA (0.6%) added to plain chow, quinapril (0.3 mg/kg) added to drinking water, and a low-calorie diet based on pair-feeding were administered to obese rats from age 4 to 20 weeks. Immunohistochemical expression of alpha-smooth muscle actin, a marker of interstitial and glomerular fibrosis and an early indicator of nephropathy, was measured semiquantitatively in glomeruli, cortical interstitium, and medullary interstitium on a scale of 0 to 4 and was reported as mean +/- SEM., Results: When compared with the obese control group, quinapril exhibited a marked reduction in alpha-smooth muscle actin staining in glomeruli, cortical interstitium, and medullary interstitium (P < 0.0005); DHEA reduced alpha-smooth muscle actin staining in cortical interstitium and medullary interstitium (P < 0. 005), and a low-calorie diet reduced alpha-smooth muscle actin staining in cortical and medullary interstitium (P < 0.005), which was similar to the effects of DHEA., Conclusions: DHEA was similar to a low-calorie diet in reducing the immunohistochemical staining of alpha-smooth muscle actin in obese Zucker rats. However, quinapril exerted a marked protective effect on the development of fibrosis, as indicated by alpha-smooth muscle actin staining, which was significantly less than that of DHEA at the doses studied.

Abnormalities of the production of dehydroepiandrosterone (DHEA), the adrenal androgen, have been linked with disorders such as obesity and psychological disorders such as major depression. Adrenocorticotropin (ACTH) is the primary stimulant of DHEA, and cortisol, from the adrenal. We chose to examine the DHEA and DHEA/cortisol response to the novel low-dose ACTH test in healthy subjects and a cohort with chronic fatigue syndrome (CFS): this test is useful in assessing subtle irregularities of pituitary-adrenal activity. Nineteen CFS subjects (diagnosed by CDC criteria) and 10 healthy subjects were examined. We demonstrated that 1 microg ACTH significantly elevates DHEA levels, with no difference in output between CFS and healthy subjects. The DHEA/cortisol ratio decreased in response to ACTH stimulation in healthy subjects but not in the CFS cohort. We suggest this divergence of response between the two groups represents an imbalance in the relative synthetic pathways of the CFS group which, if present chronically and if comparable to daily stressors, may manifest itself as an inappropriate response to stress. This difference may be important in either the genesis or propagation of the syndrome.

When allowed to select between macronutrients in a 1-h-a-day meal paradigm, Zucker rats consume 20-80% of their total caloric intake as fat. If they receive an intraperitoneal injection of DHEA 2 h before such a test meal, they consume fewer total calories. The magnitude of this effect on each macronutrient depends upon the animal's initial preference for fat; the higher the initial fat preference, the more profound is the decrease in caloric intake and the more pronounced the effect on fat consumption. Doses as low as 25 mg DHEA/kg body weight are effective. Lean Zucker rats that prefer to consume a high-fat diet have higher epinephrine and dopamine levels in select regions of the hypothalamus known to control food intake. Administration of DHEA to such animals 2 h before decapitation reduces the content of norepinephrine and these monoamines to levels that mimic the values found in the low-fat-preferring animals. It is hypothesized that exogenous DHEA causes the acute release of norepinephrine, epinephrine, and dopamine in select regions of the hypothalamus, and this release causes a decrease in food intake, particularly fat.

High free fatty acid (FFA) levels are common in obesity and in diseases such as diabetes that are associated with the obese state. Dehydroepiandrosterone (DHEA) decreases dietary fat consumption, body fat content, and insulin levels in the obese Zucker rat (ZR), a genetic model of human youth-onset obesity and type 2 diabetes mellitus. This study was conducted to investigate the effects of DHEA on lean and obese ZR serum, adipose, and hepatic tissue fatty acid (FA) profiles and serum FFA levels. Because DHEA is known to decrease fat consumption and body fat, we postulate that DHEA may also alter FA profiles and FFA levels of the obese ZR such that they more closely resemble the profiles and levels of their lean siblings. In this study there was a DHEA and a pair-fed (PF) group (n = 6) for 12 lean and 12 obese ZR. The diet of the treatment groups was supplemented with 0.6% DHEA, and PF groups were given the same average calories consumed by their corresponding DHEA group for 30 d. Fasted animals were sacrificed, and FA profiles and FFA levels were measured. Serum FFA levels were higher in obese (approximately 1 mmol/L) compared to lean rats (approximately 0.6 mmol/L). After 30 d of DHEA treatment, FFA levels were lower (P < 0.05) in both lean and obese groups. Although several significant differences in FA profile of serum, hepatic, and adipose lipid components were observed between lean and obese ZR, DHEA-related changes were only observed in the serum phospholipid (PL) and liver PL and triglyceride fractions. The slight but significant decrease in serum FFA levels may be reflected by changes in serum PL FA profiles. Specific hepatic FA profile alterations may be related to DHEA's known effects in inducing hepatic peroxisomes. We speculate that such FA changes may give insight into a mechanism for the action of DHEA.

The obese Zucker rat has a genetically flawed leptin system and is a model of hyperphagia, obesity, hyperlipidemia, and markedly elevated leptin levels. Dehydroepiandrosterone (DHEA) administration reduces hyperphagia, hyperlipidemia, and obesity in Zucker rats. Since serum leptin levels are associated with body fat, we wondered what the effects of fat pad weight reduction from DHEA administration would have on leptin levels. This experiment investigated the effects of DHEA on intra-abdominal fat pads, serum lipids, and peripheral leptin in male lean and obese Zucker rats that were administered DHEA in their food from 4 weeks of age to 20 weeks. Lean and obese rats received plain chow or chow containing DHEA. Additional chow-fed groups of lean and obese weight-matched controls and obese pair-fed rats helped to control for the reduced body weight, food intake, and fat pad weights seen with DHEA administration. DHEA administration to lean Zucker rats reduced body weight and fat pad weights, but leptin levels showed a lower trend. Among obese rats, both DHEA treatment and pair-feeding reduced body weight and fat pad weights, but only DHEA lowered leptin levels. The weight-matched controls had reductions in fat pad weights similar to the DHEA-treated group, but with increased leptin levels. Thus, DHEA may exert a small, independent effect on leptin levels in this animal model, but the reduction is less than what would be expected.

To understand the mechanism(s) of appetite modulation by DHEA, we have undertaken a series of studies to examine the effects of DHEA on neurotransmitters and neuropeptides known to affect appetitive behavior. Here, we report the effect of DHEA on serum enterostatin-VPDPR or E, a pentapeptide known to cause selective diminution in fat intake. Four-week-old lean (fa/+) and obese (fa/fa) Zucker rats were divided into control and treatment groups. DHEA-treated groups received powdered chow containing 0.6% DHEA ad lib for 16 weeks. Another group of obese rats was pair fed to match the intake of the obese DHEA-treated rats. At the end of this period, trunk blood was collected from fasted rats for assay of E-like immunoreactivity (E-LI) by ELISA. DHEA treatment caused a significant diminution in circulating E-LI in both lean (control: 2030 +/- 226; treated: 752 +/- 145 ng/mL; n = 10, p < 0.0001) and obese (control: 2489 +/- 391, n = 6; treated: 1123 +/- 185 ng/mL, n = 7; p = 0.0003) rats. Because DHEA treatment decreases caloric intake and body weight, we examined the effect of caloric intake and body weight on E-LI levels. Serum ELI levels were lower in the obese DHEA-treated group compared to that of obese pair fed (pair fed: 1589 +/- 313, n = 6; DHEA: 1123 +/- 185 ng/mL, n = 7), but the differences were statistically insignificant (p = 0.185). Also, both weight-matched lean and obese control rats had significantly (p < 0.008) higher E-LI than their DHEA-treated counterparts. To examine whether the decrease in serum E-LI following DHEA treatment could be due to increased peptide metabolism, the rate of disappearance of endogenous E-LI from serum (obese control and DHEA-treated) at 37 degrees C was evaluated. The results show an attenuation of peptide metabolism in serum from DHEA-treated rats, a finding contrary to our expectations. In summary, DHEA treatment lowers serum E-LI levels both in lean and obese Zucker rats. This decrement in peptide level is not secondary to changes in body weight or caloric intake due to DHEA, or due to altered serum peptide metabolism. Although DHEA appears to be a potent modulator of E-LI levels, the relationship between DHEA and E-LI in relation to appetitive behavior remains to be clarified.

The behavioral endpoint of open-field spontaneous activity was used to characterize further the central nervous system actions of dehydroepiandrosterone. DHEA, administered by intraperitoneal injection, causes a dose-dependent decrease in the spontaneous activity of lean and obese Zucker rats when exposed to a novel environment. The midpoint of DHEA's effect is around 50 mg/kg, a dose similar to that which reduces caloric intake of the rat by nearly 50%. d-Fenfluramine, a known anorectic agent, decreases spontaneous activity under the same conditions. Administration of either DHEA or d-fenfluramine leads to changes in serotonin or its metabolite, 5-hydroxyindole acetic acid, in select regions of the brain. These results emphasize that DHEA given peripherally can affect both the level of neurotransimitters and central nervous system function.

Fasted obese, female Zucker rats accustomed to eating a single high fat meal within 1 h a day were treated with intraperitoneal injections of dehydroepiandrosterone (DHEA) and dextrofenfluramine (d-fen), either individually or in combination. Caloric intake was measured over a 1-h period 2 h after drug administration, and results compared to that of vehicle-treated controls. At 50 mg/kg body weight, DHEA did not affect food intake. At doses of < or = 2 mg/kg d-fen did not affect food intake. Together, however, DHEA 50 mg/kg and d-fen < or = 2 mg/kg significantly decreased food intake. At doses of > or = 3 mg/kg d-fen diminished caloric intake by itself, and the addition of DHEA significantly augmented this effect. Neurotransmitter levels in select regions of the hypothalamus of animals treated using a similar drug protocol showed several changes in the levels of serotonin and its metabolite 5 hydroxyindole acetic acid (5-HIAA). It is hypothesized that DHEA augments the production of serotonin while d-fenfluramine enhances its release, and together these two actions may account for the synergistic action of DHEA and d-fenfluramine.

Background: Hyperactivity and hypoactivity of the HPA have been forwarded as of pathophysiological relevance in major depressive disorder and chronic fatigue syndrome (CFS), respectively., Methods: This study examines cortisol levels in the two disorders, and also assesses levels of the adrenal androgens, dehydroepiandrosterone (DHEA) and its sulphate derivative (DHEA-S), and 17-alpha-hydroxyprogesterone; 15 subjects with CFS diagnosed according to CDC criteria, 15 subjects with DSM III-R major depression and 11 healthy subjects were compared., Results: DHEA and DHEA-S levels were significantly lower in the CFS compared to the healthy group; DHEA-S levels, but not DHEA, were lower in the depressives; cortisol and 17-alpha-hydroxyprogesterone did not differ between the three groups., Conclusions: A potential role for DHEA, both therapeutically and as a diagnostic tool, in CFS, is suggested.

Aim: The effects of dehydroepiandrosterone (DHEA) on appetite and weight in the Zucker rat have been examined by many investigators who have reported appetite suppression and metabolic effects. However, these studies compared the treated animals to controls of a similar age. Since animals of different sizes consume different amounts of food, perhaps the treated animals should be compared to controls of a similar size. We studied the effects of DHEA on energy intake and weight gain and analysed the effects by age and metabolic body size., Methods: Lean (n = 21) and obese (n = 16) male Zucker rats were fed plain chow or chow containing 6 g DHEA/kg chow (0.6% wt/wt) from age 4 wk to 20 wk. Daily energy intakes and body weights were determined at least once weekly., Results: As expected, the lean and obese rats given DHEA exhibited less daily energy intake (kJ/d) and less weight gain than their respective controls of the same age. The lean rats given DHEA did not exhibit any difference in daily energy intake when determined relative to body weight (b.w.) (kJ x d-1 x g b.w.-1) compared to lean controls of the same metabolic body size, while the obese rats given DHEA exhibited less daily energy intake relative to b.w. (kJ x d-1 x g b.w.-1) compared to obese control of the same metabolic body size., Conclusions: Though DHEA reduced total energy intake among the lean and obese Zucker rats, only the obese rats exhibited less energy intake relative to b.w. compared to controls of the same metabolic body size. Thus, DHEA may exert different effects on energy intake relative to b.w. in lean and obese Zucker rats and perhaps the lean Zucker rat is a better model for evaluating the metabolic effects of DHEA since it does not exhibit any effect on energy intake relative to b.w. compared to rats of the same metabolic body size.

Objectives: Studies from both experimental animals and humans suggest that administration of exogenous DHEA may have beneficial endocrine-metabolic, immunologic and neurologic effects. Several groups have administered DHEA to humans, but to the best of our knowledge, no one at this point has published a summary of the relationship between the administered dose of DHEA and the serum levels of steroids attained., Design: We summarize the relationship between the administered dose of DHEA and the resulting serum level of DHEA and DHEA-S, in humans, from 18 published articles., Results: Serum levels of DHEA and DHEA-S increase with increasing doses. Doses above 50 mg/day result in levels that are at or above the upper limit of normal for healthy young adults. At doses above 300 mg/day the increment of serum DHEA and DHEA-S appears to reach a plateau., Conclusions: Those wanting to use supplemental DHEA might consider that doses of 300 mg/day are maximal; they clearly result in supraphysiologic concentrations and above this level doses may have increased side effects without significantly increasing the effective level of serum hormone.

Dehydroepiandrosterone (DHEA) is the major adrenal steroid of young adults; however, its physiologic functions, if any, are not known. The purpose of this review is to evaluate the current literature in which DHEA was administered to either humans or experimental animals to discern what these functions might be. Reports are divided into five areas: neurologic, immunologic, cardiovascular, oncologic, and metabolic. Particular attention is paid to the dosage and route of administration. This type of analysis shows that at the lowest doses, DHEA has effects on neurologic and immunologic tissues, suggesting that these two sites may be physiologic targets. DHEA also affects cardiologic and metabolic functions as well as tumor growth, but such actions require higher doses and may reflect 'pharmacologic' activities. It is proposed that DHEA's pattern of activity represents a new class of steroid hormones, the "Regnantoids." Further progress in the endocrinology of this family of steroids may only come when synthetic, long-acting analogs of DHEA are available for in vitro studies to allow correlations between hormone action and receptor binding.

The effect of dehydroepiandrosterone (DHEA) administered as an acute intraperitoneal (IP) injection on food selection and levels of hypothalamic neurotransmitters of obese Zucker rats was investigated. Animals consumed a 'macronutrient selection' diet which consisted of three separate foodstuffs; they were nearly pure selections of fat, protein or carbohydrate. On the day before DHEA treatment, food bowls were removed at 1700 h and the animals fasted. The next morning some were treated with IP DHEA (100-200 mg/kg) while the controls received vehicle. Two hours later, their food intakes over 4 h were quantitated or, in other experiments, the animals were decapitated and hypothalamic neurotransmitter levels determined. Results showed that the administration of DHEA clearly diminished the amount of fat the animals consumed while their intakes of carbohydrate and protein were unchanged. Levels of neurotransmitters in the paraventricular nuclear region were altered. It is concluded that DHEA diminishes the fat food consumption of obese Zucker rats by altering the levels of neurotransmitters in select regions of the hypothalamus.

Lean [n = 11, body mass index (BMI) < 22.5] and obese (n = 13, BMI > 31.5) women consumed a noontime meal while serum levels of cortisol and dehydroepiandrosterone (DHEA) were measured. Before the meal the obese had lower levels of serum cortisol compared to the leans. Within 20-40 min of consuming the meal the levels of cortisol rose in both groups; those of the obese rose by a greater increment and in the first postprandial hour there were no differences between lean and obese. After the meal-induced peak, the obese again had lower cortisol values. DHEA levels rose with the meal in both groups but the difference over baseline was only significant for the obese. These results show that the lean and obese respond differently to the physiologic stimulus of a meal. These results are consistent with the hypothesis that obesity is influenced by differences in adrenal function that are demonstrable during stimulation with a meal.

Background: It has been previously shown that food intake elevates circulating ACTH and cortisol levels, but no report has been published regarding the changes in circulating dehydroepiandrosterone (DHEA). DHEA was originally described as a weak androgen, but more recently it has been associated with a wide range of metabolic functions. In addition, previous studies have described a hyper-responsive hypothalamo-pituitary-adrenal axis in obese subjects in response to various stimuli, but the specific response to food has not been studied., Subjects and Design: We studied the effect of food on the hypothalamo-pituitary-adrenal axis in 20 subjects of normal body mass index (BMI range 18-25) and also in a group of 12 obese subjects (BMI range 34-61). Levels of glucose, insulin, ACTH, cortisol and dehydroepiandrosterone were measured every 20 minutes., Results: A small rise in DHEA accompanies the rise in circulating ACTH and cortisol in response to food in both lean and obese subjects, but DHEA rose independently of cortisol and ACTH on the fasting day. In the obese subjects, food induced a significantly greater change in serum cortisol (peak cortisol rise (mean +/- SEM); normal-weight group, 169 +/- 14%; obese group, 294 +/- 23%) and in the cortisol/DHEA ratio (area under the curve; normal-weight group, 202 +/- 15%; obese group, 292 +/- 29%) than in the normal-weight subjects. This difference was particularly notable in those with central-type obesity (waist/hip ratio > 0.80). A group of the normal, jean female subjects showed no cortisol rise after food intake., Conclusion: Our results suggest that DHEA may vary independently of circulating cortisol, and that the cortisol response to food is enhanced in obese subjects, particularly in those with central obesity. We speculate that there may be a caused connection between the cortisol response to food in normal subjects, and the subsequent distribution of fat if such subjects overeat sufficiently to become obese.

Zucker rats are a frequently used model in obesity research. Dehydroepiandrosterone (DHEA) reduces their rate of weight gain and caloric consumption. So far, most studies have been conducted while the animals consume laboratory rodent chow, which is low in fat. In the experiments of this communication, Zucker rats were offered fat as a food choice. The goal was to determine how the consumption of fat would affect their weight gain and what effect DHEA would have on macronutrient selection. It was found that Zucker rats both male and female, lean and obese selected nearly 40% of their calories as fat when allowed to choose from nearly pure carbohydrate, protein, and fat foodstuffs. Consuming these three macronutrient diets they ate more calories and gained more weight than chow-fed controls over short periods of time. DHEA administered as an intraperitoneal injection decreased caloric intake of Zuckers. This decrement was quantitatively most important on fat intake. DHEA also prevented weight gain. It is concluded that the availability of fat food affects weight gain in Zucker rats and that DHEA modifies the selection of food such that Zucker rats eat less fat.

Objectives: To investigate whether dehydroepiandrosterone (DHEA), an adrenal/gonadal androgen, can act centrally to reduce energy intake in a model of genetic obesity, the Zucker fatty rat. To investigate a possible mechanism of action., Design: Two experiments were performed in lean and obese female Zucker rats. In the first experiment, 24 h following administration of i.p. DHEA (200 mg/kg), three hypothalamic regions [lateral hypothalamus (LH), ventromedial nucleus (VMH), and paraventricular nucleus (PVN)] were analyzed for monoamine neurotransmitter concentrations. In the second experiment, DHEA (50 micrograms) was administered by i.c.v. injection. Energy intake for the following day was measured., Measurements: In the first experiment, concentrations of norepinephrine (NE), epinephrine (EPI), dopamine (DA), serotonin (5HT), the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured. Ratios of 5HT/5HIAA were calculated. In the second experiment, kilojoules consumed per 24 h were calculated., Results: All LH monoamines, and PVN DA, displayed lower concentrations in obese than lean control rats. DHEA treatment reversed these reductions in obese rats without affecting lean rats. DHEA increased VMH EPI in obese rats only. DHEA increased PVN NE in both lean and obese rats. I.C.V. DHEA decreased energy intake in obese but not lean rats., Conclusion: The i.c.v. results suggest that DHEA exerts a phenotype specific, centrally mediated inhibitory effect on food intake. In addition, in doses previously shown to reduce energy intake in obese but not lean rats, i.p. DHEA reversed reduced concentrations of many monoamines, particularly in the LH, in obese animals only. These latter changes provide indirect evidence to suggest that these central neurotransmitters may play an important role in the antiobesity effect of DHEA in the Zucker fatty rat.

The effect of dehydroepiandrosterone (DHEA) on the macronutrient preference and total energy intake of lean and obese female Zucker rats was studied. Introduction of DHEA led to a rapid decrease in the consumption of fat, protein and total calories by the obese rat. DHEA treatment of the lean rat caused a change neither in its total energy consumption nor in its fat consumption, but did cause a distinct expression of preference for carbohydrate over protein. Both lean and obese animals gained weight rapidly during the steroid-free weeks and lost weight while consuming the DHEA-supplemented diet. The difference in weight changes seen with the obese rats between the DHEA-free and DHEA-supplemented periods could be accounted for by differences in caloric intake. Lean rats, however, did not change their total energy intake during DHEA-treatment periods; therefore, DHEA caused weight loss in the lean rat probably by altering energy metabolism. It is concluded that in the obese, young, female Zucker rat, DHEA alters macronutrient preference as well as caloric intake. In the lean rat, DHEA has a more subtle effect on relative macronutrient preference and not on total energy consumption.

Objective: Dehydroepiandrosterone (DHEA) decreases body weight and food intake of the obese Zucker rat, a model of youth-onset obesity associated with hyperphagia. The effects of discontinuing DHEA treatment on these parameters, however, has not been investigated. This question was studied in rats that had been maintained on DHEA-supplemented (0.0%, 0.06%, 0.15%, 0.3% or 0.6%) diets for 7 days., Method: The results were correlated with regional levels of hypothalamic neurotransmitters in rats treated with 0.6% DHEA for 7 days in a separate experiment. Neurotransmitter changes were evaluated after Day 0 (7 days of treatment), and Day +1 and Day+2 post-DHEA., Results: Upon removing dietary DHEA, rats immediately (+1 day) consumed significantly more food than while on the DHEA-supplemented diet. Indeed, they consumed even more food than the group that had always been on the DHEA-free diet. This intake above control lasted for as long as +9 days post-DHEA treatment. After 7 days of DHEA treatment, lateral hypothalamic (LH) serotonin (5-HT) and dopamine (Dpm) were elevated significantly (P < 0.05) immediate changes in 5-HT and Dpm returned to baseline by day 2 of post-DHEA treatment. No significant changes occurred in either the ventromedial hypothalamus (VMH) or the paraventricular nucleus (PVN)., Conclusions: These observations suggest that there is a possible relationship between increases of LH 5-HT and Dpm with 0.6% DHEA treatment. Both are inhibitory to food intake and DHEA at the 0.6% dose causes hypophagia after 7 days of treatment (i.e. 0 days). Subsequent decreases of these monoamines occurred during the post-DHEA period at both +1 and +2 days. Return of these inhibitory monoamines to baseline could be responsible for reversal of the hypophagia, however, they do not rule out the production of a separate stimulator of food intake.

Dehydroepiandrosterone (DHEA) has been reported to exert antiglucocorticoid activity. When administered to obese, hypercorticosteronemic Zucker rats, it causes a diminution of food intake and a reduction in their rate of weight gain. This experiment was conducted to evaluate whether this biologic effect could be ascribed to chronic adrenal insufficiency. Obese and lean Zucker rats were treated with DHEA as a food supplement for 28 days. Upon sacrifice, organ weights and serum chemistries were measured, along with neurotransmitter levels in regions of the hypothalamus. Results showed that although the obese animals gained weight more slowly, had lower insulin levels, and ate less, their serum glucose, corticosterone, and ACTH levels were not different from control. Hypothalamic neurotransmitters in the obese rat were unaffected by chronic DHEA treatment. We concluded that, although DHEA clearly affects Zucker weight gain, it does not induce chronic adrenal insufficiency.

Dehydroepiandrosterone (DHEA) reduces food intake in obese Zucker rats. To study the role of taste aversion on this process, we used two approaches. First, we presented increasing concentrations of DHEA in chow to lean and obese Zucker rats, either in competition with unadulterated chow, or alone. Second, we examined energy intake following parenteral DHEA administration. Both lean and obese rats always preferred nonadulterated chow to DHEA-supplemented chow. However, lean rats required a higher DHEA concentration (0.06%) than obese rats (0.015%) to achieve the same degree of aversion. When DHEA-supplemented chow was presented alone, only high concentrations (0.3 and 0.6% DHEA) decreased food intake. Rats given DHEA by IP injection (200 mg/kg/day) also decreased their energy intakes. The results demonstrate that although DHEA can cause taste aversion at low concentrations in Zucker rats, it does not alter energy intake until high concentrations are given. In addition, nonoral DHEA also decreases energy intake in these animals. These results suggest that DHEA's antiobesity effect is not mediated by taste aversion.

Dehydroepiandrosterone (DHEA) decreases the activity of hepatic tyrosine aminotransferase (TAT), a glucocorticoid-inducible enzyme, in the obese, hypercorticosteronemic Zucker rat. To investigate the mechanism of this antiglucocorticoid action, the effect of exogenous DHEA on hepatic glucocorticoid receptor (GC) number and affinity was quantitated. Food supplementation with DHEA (0.6% w/w) for 1 or 7 days had no effect on either receptor number or affinity in obese Zucker rats. After 28 days, however, DHEA treatment resulted in a nearly 40% decrease in cytosolic hepatic receptor content (Bmax; fmol/mg cytosolic protein) without any change in affinity (Kd) in both lean and obese rats. DHEA treatment for 28 days also resulted in an increased liver size and cytosolic protein content. When the hepatic GC receptor content was normalized based on the change in liver size and protein content, the apparent number of GC binding sites per liver was not affected by DHEA treatment. This observation suggests that DHEA's effect on GC receptor content may not be a specific action and that downregulation of the GC receptor is not the mechanism of DHEA action on GC induced TAT activity. This is supported by the effect of DHEA on obese rat TAT activity in the same experiment where the greatest inhibition occurred after only 1 day of treatment. From these experiments it is concluded that although long-term DHEA treatment may decrease the relative concentration of GC receptors in rat liver, this change is not the mechanism through which DHEA mediates its acute antiglucocorticoid action.

The obese Zucker rat is a model of youth-onset obesity associated with hyperphagia. In this study, dehydroepiandrosterone's effect at decreasing food intake and body weight in the obese Zucker rat was investigated. Rats were treated with a dehydroepiandrosterone-supplemented diet (0.0, 0.06, 0.15, 0.3, or 0.6%) for 7 days. The 0.3 and 0.6% treatment groups showed a dramatic decrease in daily food intake, which was evident the 1st day. In addition to the reduction in food intake, body weight changes also were affected significantly in the high-dose treatment groups. The possibility that these dehydroepiandrosterone-induced changes were correlated to perturbations in central neurotransmitter levels associated with appetite control was investigated. The hypothalamus, frontal cortex, striatum, and hippocampus of dehydroepiandrosterone-treated animals were assayed for neurotransmitters known to have inhibitory or stimulatory effects on feeding behavior (serotonin, dopamine, norepinephrine, and epinephrine). Significant differences from steroid-free controls were noted only in the levels of hypothalamic serotonin in animals treated with dehydroepiandrosterone. Serotonin in the hypothalamus has been shown to decrease feeding behavior. The magnitude of dehydroepiandrosterone's effect on hypothalamic serotonin correlated with its effect on feeding behavior. Thus, dehydroepiandrosterone may reduce hyperphagia by altering hypothalamic levels of serotonin.

Human immunodeficiency virus (HIV) is a major cause of immunoincompetence. Whether the virus, itself, accounts for all the deficiency remains in question. Steroids can also influence immune function; glucocorticoids cause immunoincompetence while dehydroepiandrosterone (DHEA) enhances immune function. Changes in the levels of such hormones during the course of HIV illness might result in significant changes in immune competence. The purpose of this study is to investigate whether dehydroepiandrosterone-sulphate (DHEA-S) or cortisol levels correlate with absolute CD4 lymphocyte levels. Plasma for cortisol and DHEA-S was drawn from 98 adults with HIV. Of these, 67 had simultaneous CD4 levels. Cortisol levels were 12.4 +/- 4.6 micrograms/dl, DHEA-S 262 +/- 142 micrograms/dl, and CD4 levels were 308 +/- 217/mm3 (mean +/- SD). Correlational analysis revealed a significant relationship between DHEA-S and CD4 levels (r = 0.30; p = 0.01) but not between CD4 levels and cortisol (r = 0.11; p = 0.36) or cortisol/DHEA-S ratios (r = 0.17; p = 0.16). When analyzed by clinical subgroups, significant differences were also found with a decrease in DHEA-S levels seen in persons with more advanced illness. The data exhibit a positive relationship between the immune status of patients with HIV-related illness and DHEA, leading to the hypothesis that DHEA deficiency may worsen immune status.

Oral dehydroepiandrosterone (DHEA) causes weight loss in the obese Zucker rat. To study this process, we fed lean and obese female Zucker rats either control chow diets alone or diets containing 0.6% DHEA for 4 weeks. DHEA treatment led to a significant increase in the caloric intake of lean-treatment rats and a significant decrease in obese-treatment rats compared to their respective controls. These phenotype-specific divergent effects began acutely and were sustained. The energy intake changes with DHEA treatment were significant after correcting for body weight. Divergent effects of DHEA were also observed in body weight changes and in the food efficiency ratios of the animals; DHEA affected obese rats but not lean ones. The results of the present study suggest that the appetite component of DHEA's antiobesity effect in the Zucker fatty rat cannot be discounted.

Dehydroepiandrosterone (DHEA) reduces weight gain in the hypercorticosteronemic Zucker fatty rat, an animal model of genetic obesity. However, the mechanism of action of DHEA is still unclear. We propose that DHEA acts as an antiglucocorticoid in the Zucker fatty rat. To test this hypothesis we examined DHEA's ability to block the activation of the glucocorticoid-inducible enzymes tyrosine aminotransferase (TAT) and ornithine decarboxylase (ODC) by dexamethasone (i.p. 5 micrograms/100 g body weight) in hepatic tissue of 6-10 week old Zucker rats. Injections of DMSO, the vehicle, served as a control. DHEA alone did not affect TAT, but when DHEA (500 micrograms/100 g b.w.) was administered simultaneously with dexamethasone, activation did not occur. Similar results were seen using a second tissue (kidney). We conclude that DHEA can act acutely as an antiglucocorticoid in the young obese Zucker rat and hypothesize that its chronic anti-obesity effect may reflect, at least in part, a chronic antiglucocorticoid activity.

The acute effect of dehydroepiandrosterone (DHEA) and its conjugate, DHEA-sulfate (DHEA-S) on glucocorticoid action was tested in vivo using male Swiss-Webster mice. The authors found that DHEA and DHEA-S significantly inhibited induction of hepatic tyrosine aminotransferase activity, although the former was more potent. This inhibition was dose- and time-dependent and was not demonstrable with other steroids. The same inhibitory effect of DHEA was seen with kidney tyrosine aminotransferase induction, as well as with liver and kidney ornithine decarboxylase enzyme activity, another glucocorticoid-induced enzyme. The conclusion is that DHEA acts acutely as an antiglucocorticoid and exerts its effect in different glucocorticoid-sensitive systems.