Frank Svec

Glucocorticoid receptor regulation

Glucocorticoids, like other classes of steroid hormones, must bind to cellular receptors in order to exert their effects. Because of this central role in mediating hormone action, it is important to elucidate those factors that control receptor content. The purpose of this minireview is to summarize the recent work that explores the mechanisms through which cells modulate their glucocorticoid receptor binding capacity.

The Relationship of Serum DHEA-S and Cortisol Levels to Measures of Immune Function in Hufman Immunodeficiency Virus-Related Illness

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.

The effect of dehydroepiandrosterone (DHEA) on zucker rat food selection and hypothalamic neurotransmitters

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.

THE EFFECT OF DHEA GIVEN CHRONICALLY TO ZUCKER RATS

Abstract 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.

Divergent effect of dehydroepiandrosterone on energy intakes of Zucker rats

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 DHEAs antiobesity effect in the Zucker fatty rat cannot be discounted.

The acute effect of a noontime meal on the serum levels of cortisol and DHEA in lean and obese women

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.

Does taste aversion play a role in the effect of dehydroepiandrosterone in zucker rats

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 DHEAs antiobesity effect is not mediated by taste aversion.

Can associations between free fatty acid levels and metabolic parameters determine insulin resistance development in obese Zucker rats

Elevated levels of serum free fatty acids (FFA) may be the metabolic alteration in obesity that leads to insulin resistance (IR) and type 2 diabetes mellitus (DM). The obese Zucker rat (ZR) is a genetic model of juvenile-onset obesity and type 2 DM. Compared with its lean sibling, the obese ZR is hyperinsulinemic, hypertriglyceridemic, and, beginning at about 6 months, hyperglycemic. The obese ZR demonstrates also IR, hyperphagia, increased lipogenesis, adipocyte hypertrophy and hyperplasia, and increased serum FFA levels. This study was designed to determine if serum FFA levels in lean and obese ZRs correlate with metabolic parameters associated with altered energy metabolism and IR. We hypothesized that serum FFA levels correlate with such serum parameters such as insulin, glucose, triglyceride, and total cholesterol, as well as such tissue parameters as retroperitoneal, perirenal, and epididymal fat pad weights and liver total lipid content. Twenty lean and 20 obese ZR were age/weight matched. For 14 days each rat had ad libitum access to a single bowl diet that was 50% fat, 30% carbohydrate, and 20% protein. Body weights and caloric intakes were measured daily. After 14 days, all animals were fasted overnight and euthanized. Serum and tissue measurements were made and various parameters were correlated with FFA levels. Serum FFA levels were almost 2 times higher in the obese ZR (approximately 1 mmol/L) compared to the lean (approximately 0.6 mmol/L). Each variable measured was significantly (p < or = 0.05) greater in the obese ZR compared to the lean. There were significant correlations between serum FFA levels and certain variables when data from all ZR were plotted against serum and tissue parameters. However, within phenotypes, there were no significant correlations. Serum FFA levels predict serum and tissue parameters that accompany obesity and IR when comparing lean and obese rats. However, FFA do not predict such parameters within one phenotype.

Synergistic Anorectic Effect of Dehydroepiandrosterone and d-Fenfluramine on the Obese Zucker Rat

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.

Dietary and hypothalamic changes in Δ4-androstenedione-treated Zucker rats

Dehydroepiandrosterone (DHEA) has been shown to alter hypothalamic monoamines and reduce energy intake (EI) in Zucker rats (ZRs). We hypothesized that a metabolite of DHEA, delta 4-Androstenedione (delta 4), may mediate these effects. Male lean and obese ZRs (LZR, OZR) were fed control chow (CC) for 7 days, during which basal EI was recorded, various concentrations of delta 4 for 7 days, during which 0.6 and 0.3% delta 4 reduced EI significantly, and CC for 7 days, which resulted in a return of EI to basal levels. After delta 4 administration, neurotransmitter contents of various hypothalamic areas were determined. Serotonin (5-HT) has been shown to be correlated with feeding inhibition, and we have shown DHEA to increase lateral hypothalamic 5-HT synthesis; however, after 1 day and 7 days of delta 4, the OZR exhibited an increased metabolism, not synthesis, of 5-HT in the lateral and paraventricular hypothalamus, respectively, delta 4 was compared to DHEA in a macronutrient self-selection study with female OZRs. One group was injected intraperitoneally (IP) with sesame oil (control), another with DHEA (100 mg/kg), and another with delta 4 (100 mg/kg). Previous studies have shown that DHEA decreases both EI and % calories from fat. In this study, delta 4 decreased % calories from fat, but did not decrease total EI. Contrary to DHEAs effect of reducing serum insulin through 28 days of treatment, delta 4 in chow reduced insulin only acutely (1 day). We conclude, based on these differences, that DHEA has unique effects not mediated by its metabolite, delta 4-Androstenedione.