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. Under normal physiological conditions, the type I receptor is tonically activated, either by low basal levels of circulating CORT (0.5-2 microgram %) normally available across the circadian cycle or possibly by the mineralocorticoid aldosterone. This type I activation is required for the maintenance of fat ingestion and fat deposition that occurs during most meals of the feeding cycle. In contrast, the type II receptor is phasically activated by moderate levels of CORT (2-10 micrograms %) normally reached during the circadian peak. Activation of this receptor is required for the natural surge in carbohydrate ingestion and metabolism that is essential at the onset of the active feeding cycle when the body's glycogen stores are at their nadir, and gluconeogenesis is needed to maintain blood glucose levels. This receptor is also activated during periods of increased energy requirements, such as, after exercise and food restriction, when CORT levels rise further (> 10 micrograms %) and when its catabolic effects on fat and protein stores predominate to provide additional substrates for glucose homeostasis. These functions of CORT on fat and carbohydrate balance are mediated, in part, by type I and type II receptors located within the hypothalamic paraventricular nucleus, which is known to have key functions in controlling nutrient intake and metabolism, as well as circulating CORT levels. Moreover, the type II receptors within this nucleus, in addition to the arcuate nucleus, may interact positively with the peptide, neuropeptide Y, and the catecholamine, norepinephrine, both of which act to enhance natural carbohydrate feeding and CORT release at the onset of the natural feeding cycle. Thus, under normal conditions, endogenous CORT has a primary function in controlling nutrient ingestion and metabolism over the natural circadian cycle, through the coordinated action of the type I and type II steroid receptor systems. Through this action, CORT has impact on total caloric intake and body weight gain over the long term.(ABSTRACT TRUNCATED AT 400 WORDS)

Glucocorticoid receptors in PVN: interactions with NE, NPY, and Gal in relation to feeding.

Norepinephrine (NE) and neuropeptide Y (NPY) potentiate carbohydrate ingestion after injection into the paraventricular nucleus (PVN), whereas injection of galanin (Gal) potentiates fat intake. The present study examines the relation between these neurochemically induced feeding behaviors and the adrenal steroids acting locally within the PVN. Results demonstrate that PVN NE- and NPY-induced carbohydrate intake is abolished by adrenalectomy surgery (ADX) and by local PVN implants of the type II receptor antagonist RU-486. Carbohydrate intake in response to PVN NE or NPY injection is unaffected by the type I antagonist RU-28318. In contrast, the stimulatory effect of PVN Gal injection on fat intake is unchanged by surgical ADX or by PVN administration of RU-486 or RU-28318, suggesting that the stimulatory action of Gal on fat ingestion occurs independently of corticosterone (Cort) and of PVN type I or type II steroid receptors. It is concluded that endogenous Cort has a permissive effect on the carbohydrate feeding responses elicited by NE and NPY in the PVN and that this interaction is mediated by type II glucocorticoid receptors within this nucleus.

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 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.

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.

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.

Galanin inhibits insulin and corticosterone release after injection into the PVN.

The neuropeptide galanin (GAL, 1 microgram/0.3 microliters) was injected into the paraventricular nucleus (PVN) at two different times of the 12:12 h light/dark cycle, namely 2 h before the dark ('pre-dark') and before the light ('pre-light') periods. Blood samples were collected 15 min after injection and examined for serum levels of insulin (INS), corticosterone (CORT) and glucose (GLUC). Results indicate that PVN GAL injection in the pre-dark period strongly inhibits both CORT and INS release but has no effect on GLUC levels. These hormone changes, however, were not detected in the blood samples collected in the pre-light period. At this time, baseline levels of CORT were significantly lower than in the pre-dark period, while INS and GLUC levels were generally similar at both time periods. These results indicate that the effects of PVN GAL on CORT and INS secretion are inhibitory in nature and are temporally linked to the diurnal cycle.

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.

Nocturnal patterns of macronutrient intake in freely feeding and food-deprived rats.

Analyses of rats' feeding behavior at the start and the end of the nocturnal cycle have revealed dramatic alterations in macronutrient intake over time. At dark onset, rats displayed a preference for carbohydrate, with the first meal of the night consisting of approximately 60% of this nutrient. This carbohydrate intake was soon followed by a shift toward protein-predominant meals. Superimposed on this pattern of meal-to-meal shifts in nutrient selection appears to be an additional rhythm in which carbohydrate ingestion was favored at dark onset and protein and fat ingestion were favored during the late dark hours. Differential feeding patterns were also apparent following mild food deprivation. A 2-h period of deprivation at dark onset produced a strong compensatory feeding response, particularly of fat and carbohydrate. This pattern was not observed at the end of the dark, when little compensatory feeding was demonstrated. It is suggested that these feeding patterns may be related to the activity of certain hypothalamic neurotransmitters, e.g., norepinephrine and serotonin, known to be important in modulating temporal feeding patterns and nutrient intake.

Effects of PVN galanin on macronutrient selection.

The neuropeptide galanin (GAL), after injection into the hypothalamic paraventricular nucleus (PVN), elicited a potent feeding response. In satiated rats maintained on pure macronutrient diets (protein, carbohydrate and fat), PVN GAL injection was found to cause a preferential increase in the consumption of the fat diet, with a significantly smaller increase in carbohydrate intake and no change in protein ingestion. When the fat diet was removed, GAL's stimulatory effect on carbohydrate ingestion was reliably and selectively enhanced. These effects of GAL stand in contrast to those of neuropeptide Y (NPY), which is co-localized with NE in the PVN and which induced in these animals a strong and selective enhancement of carbohydrate intake after PVN injection. Similarly, PVN NE, known to act via alpha 2-noradrenergic receptors, induced feeding specifically of carbohydrate and, to a small extent, fat. These differential results demonstrate the specificity of the effects of the peptides (GAL and NPY) and NE on macronutrient selection, all of which can be repeatedly observed in the same group of animals and which appear to be unrelated to the rats' natural 24 hr baseline preferences. However, we did observe a strong positive correlation between NE- and GAL-induced carbohydrate intake. In light of this relationship and additional pharmacological evidence linking GAL- and NE-induced feeding, it is proposed that the effects of GAL on macronutrient selection may be mediated, at least in part, by the alpha 2-noradrenergic feeding system within the PVN.