Donna L. Tempel

Adrenal Steroid Receptors: Interactions with Brain Neuropeptide Systems in Relation to Nutrient Intake and Metabolism

The glucocorticoid, corticosterone (CORT), is believed to have an important function in modulating nutrient ingestion and metabolism. Recent evidence described in this review suggests that the effects of this adrenal hormone are mediated through two steroid receptor subtypes, the type I mineralocorticoid receptor and the type II glucocorticoid receptor. These receptors, which have different affinities for CORT, respond to different levels of circulating hormone. They mediate distinct effects of the steroid, which can be distinguished by the specific nutrient ingested and by the particular period of the circadian cycle.

Diurnal variations in the feeding responses to norepinephrine, neuropeptide Y and galanin in the PVN.

The feeding responses elicited by injection of norepinephrine (NE), neuropeptide Y (NPY) and galanin (GAL) into the paraventricular nucleus (PVN) were studied at two different times of the dark (active) cycle in male Sprague-Dawley rats maintained ad lib on pure nutrient diets. The feeding response elicited by NE in the PVN, characterized by a potent and selective stimulatory effect on ingestion of the carbohydrate diet, was significantly stronger during the early dark period (+11.7 kcal over vehicle baseline) relative to the late dark period (+7.6 kcal). A similar pattern of effects was observed with NPY in the PVN, which also selectively potentiated carbohydrate ingestion. The effects of GAL were different from those observed with NE and NPY. Whereas the total amount of food consumed after PVN GAL injection was similar in the early and late dark periods, the macronutrient selection patterns exhibited at these two times were different. During the early dark period, PVN GAL had a small stimulatory effect on carbohydrate, in addition to a strong enhancement of fat intake; in the late dark period, in contrast, GAL stimulated intake only of the fat diet. These findings may reflect differential functions of these hypothalamic neurotransmitters in controlling nutrient ingestion at different periods of the circadian cycle.

Norepinephrine in the paraventricular nucleus stimulates corticosterone release

Hypothalamic cells containing corticotropin-releasing factor are believed to be densely innervated by noradrenergic terminals. However, the role of norepinephrine (NE) in the control of the hypothalamo-pituitary-adrenal axis has remained undefined, with both excitatory and inhibitory effects suggested by the literature. The present experiments tested the effects of direct hypothalamic infusion of NE on the release of corticosterone (CORT) in awake and freely moving rats. Norepinephrine infusion into the paraventricular nucleus (PVN) produced a dose-dependent increase in circulating levels of CORT. In a mapping study, this stimulatory effect of NE was found to be anatomically localized. The strongest rise in CORT levels (up to 12 micrograms%) was observed after injection into the PVN, where NE acted in a dose-dependent fashion. A somewhat smaller effect was also detected with NE in the dorsomedial nucleus, while no response occurred after injection just dorsal to the PVN, into the ventromedial or supraoptic nuclei, or into the lateral or posterior hypothalamus. Serotonin infusion into the PVN produced a small but statistically reliable increase in circulating CORT levels. However, dopamine injection into this nucleus had no observable effect. These results agree with recent studies suggesting an excitatory function of PVN NE in the pituitary-adrenal axis.

PVN steroid implants: Effect on feeding patterns and macronutrient selection

The glucocorticoid corticosterone (CORT) plays a major role in feeding behavior, body weight regulation and metabolism. Recent work has demonstrated an interaction between circulating CORT and the alpha 2-noradrenergic feeding system of the hypothalamic paraventricular nucleus (PVN) and the existence of two different subtypes of glucocorticoid receptors in this nucleus. To examine the function of these specific PVN receptors, crystalline CORT and other steroid hormones were implanted directly into the PVN, and feeding patterns and macronutrient selection, of freely feeding adrenalectomized (ADX) and sham rats, were monitored at the beginning and end of the nocturnal feeding cycle. Results indicate that PVN CORT implants stimulate carbohydrate intake in ADX rats, at the onset of the dark cycle when the feeding-suppressive effects of ADX are strongest. Corticosterone was ineffective in sham rats and was also ineffective in potentiating food intake in ADX rats at the end of the dark phase. In contrast, implants of the mineralocorticoid aldosterone (ALDO) stimulated the ingestion of the fat diet, in both sham and ADX rats and during both the early and the late dark periods. Implants of ALDO also enhanced carbohydrate intake, but only in ADX rats and at dark onset. While the synthetic glucocorticoid, dexamethasone, had a small carbohydrate stimulatory effect similar to CORT, other steroids (deoxycorticosterone, progesterone and estrogen) were without effect. These results indicate a central site of action for the adrenal hormones in modulating nutrient intake. Based on a variety of evidence, it is suggested that the stimulatory effects of ALDO and CORT on macronutrient intake may be differentially mediated by Type 1 and Type 2 steroid receptor subtypes within the brain.

Effects of adrenal steroid agonists on food intake and macronutrient selection

These experiments tested the effects of subcutaneous (SC) and paraventricular nucleus (PVN) administration of the steroid receptor agonists, corticosterone (CORT), aldosterone (ALDO), RU28362, and dexamethasone (DEX), on food intake and macronutrient selection during the first h of the dark feeding period in the rat. Results indicate that CORT and the selective type II receptor agonist RU28362 specifically stimulate carbohydrate ingestion after SC or PVN administration, while DEX has no effect on feeding. This selective effect of SC CORT on carbohydrate ingestion is dose dependent, seen at doses ranging from 0.125 to 2.0 mg/kg. Moreover, the stimulatory effects of CORT and RU28362 on carbohydrate intake are observed in ADX rats but not in sham rats. This is in contrast to SC and PVN administration of the type I receptor agonist ALDO, which specifically enhances fat ingestion in both sham and ADX rats. These results, with both peripheral and central steroid administration, reveal selective effects of type I and type II receptor stimulation on fat and carbohydrate intake, respectively.

Adrenal Steroid Receptors in the PVN: Studies with Steroid Antagonists in Relation to Macronutrient Intake

These studies tested the impact of steroid receptor antagonists on food intake induced by steroid agonists implanted into the paraventricular nucleus (PVN) and also on feeding that naturally occurs at the onset of the active (dark) period in the rat. Implants of corticosterone (CORT) or the selective type II agonist RU28362 in the PVN stimulated feeding in adrenalectomized (ADX) rats, specifically by enhancing carbohydrate ingestion. This feeding response induced by CORT or RU28362 was blocked by PVN implants of the type II antagonist RU486 but was unaffected by the type I antagonist RU28318. In contrast, the type I agonist aldosterone (ALDO) in the PVN stimulated feeding in both sham and ADX rats by preferentially enhancing fat ingestion, which could be inhibited by the type I antagonist RU28318 but not by the type II antagonist RU486. These results indicate that the feeding elicited by CORT at dark onset is dependent upon the functional integrity of type II glucocorticoid receptors within the PVN, in contrast to the feeding elicited by ALDO which is dependent upon endogenous type I steroid receptor activation within this nucleus. Test results with these antagonists alone in freely feeding animals support a functional role for these PVN steroid receptors in adrenal steroid control of natural food intake. Specifically, blockade of PVN type II receptors with RU486 in intact rats selectively suppressed spontaneous carbohydrate feeding at dark onset, while PVN implants of the type I receptor antagonist RU28318 caused a suppression of spontaneous fat intake.(ABSTRACT TRUNCATED AT 250 WORDS)

The paraventricular nucleus is uniquely responsive to the feeding stimulatory effects of steroid hormones

The paraventricular nucleus is uniquely responsive to the feeding stimulatory effects of steroid hormones (Tempel, D.L., Kim, T. and Leibowitz, S.F. Brain Research 00: 000-000). This study tested the effects of hypothalamic as well as extrahypothalamic implants of the adrenal steroids, corticosterone (CORT) and aldosterone (ALDO), on food intake and macronutrient selection in sham-operated and adrenalectomized (ADX) rats 1 h after administration. Consistent with a previous experiment, implants of CORT and ALDO in the hypothalamic paraventricular nucleus (PVN) were effective in stimulating food intake. These tests, conducted at the onset of the active feeding cycle, showed PVN implants of CORT to potentiate specifically carbohydrate intake in ADX rats, while having no effect in sham rats. This was in contrast to PVN ALDO which predominantly stimulated fat intake in sham as well as ADX rats. Neither CORT nor ALDO had any effect on food intake after implantation into other hypothalamic or extrahypothalamic sites tested. These unresponsive hypothalamic sites were the dorsomedial and ventromedial nuclei, perifornical lateral hypothalamus, and arcuate nucleus. Extrahypothalamic sites including the dorsal CA1 region of the hippocampus, the central nucleus of the amygdala and the lateral septum were also unresponsive to steroid implants. These results identify the PVN, and the steroid receptors located within it, as having a specific function in mediating the action of CORT and ALDO on carbohydrate and fat intake, respectively.

Effects of adrenalectomy on macronutrient selection patterns in the rat

The present studies examined the effects of adrenalectomy (ADX) on nutrient selection of rats over the 24-h period, as well as during the first 2 h of the nocturnal feeding cycle. Results indicate that ADX, in rats showing generally similar preferences for carbohydrate and fat, equally suppresses intake of both of these nutrients over the 24-h period. The relative impact of ADX on carbohydrate and fat intake may shift depending upon baseline, with carbohydrate-preferring rats showing a stronger decrease in intake of this diet after ADX and fat-preferring rats exhibiting a greater decline in fat intake after ADX. Acute injections of corticosterone (CORT) and aldosterone (ALDO) are both found to restore carbohydrate as well as fat intake to ADX rats over the 24-h period. However, in the first 2 h of the dark feeding cycle, carbohydrate intake is found to be selectively suppressed after ADX, and CORT injection (0.5 and 2.0 mg/kg, SC) restores carbohydrate intake during this early dark period, while producing a small increase in fat intake only at the higher dose. This is in contrast to ALDO administration at dark onset, which has a stronger stimulatory effect on fat intake in the ADX rat but does not fully restore carbohydrate intake. These findings indicate that CORT and ALDO have differential effects on nutrient intake in ADX rats particularly at the onset of the dark cycle, and it is suggested that these effects are mediated, respectively, by the type I and type II steroid receptor systems in the brain.