Glucocorticoids are Required for Food Deprivation‐Induced Increases in Hypothalamic Neuropeptide Y Expression

Abstract

Neuropeptide Y (NPY), a 36 amino-acid peptide found within the hypothalamus, is thought to be an important regulator of food intake. Hypothalamic NPY gene expression, synthesis and secretion are all known to be increased in models of increased metabolic demand in which serum glucocorticoids are also elevated. The present studies were designed to test the hypothesis that glucocorticoids are required for increased hypothalamic preproNPY mRNA levels induced by food deprivation (FD). First, animals underwent bilateral sham-adrenalectomy (sham) or not (control), and were subjected to 72 h FD, or not. Total RNA was isolated from hypothalamic tissue blocks and the content of preproNPY mRNA was measured by solution hybridization/RNase protection analysis. This study revealed that there was no significant difference in hypothalamic preproNPY mRNA content between shamfed and control-fed groups, or between sham-FD and control-FD groups. In the second experiment, animals underwent bilateral adrenalectomy (ADX), were allowed to feed ad libitum and were sacrificed 1 day, 4 days and 7 days after ADX. Nuclease protection analysis revealed no significant effect of ADX on hypothalamic preproNPY mRNA levels over this time-course. Finally, we examined the role of glucocorticoids in regulating NPY gene expression following FD. Animals underwent bilateral ADX, or not. At the time of surgery, ADX animals received placebo, or corticosterone (B) replacement in the form of constant release pellets, at one of two doses. Food was removed from half of the animals in each group 24 h after surgery; all animals were sacrificed 72 h thereafter. There was no difference in preproNPY mRNA content between the ADX-FD and ADX-fed groups, relative to the fed controls. Replacement with corticosterone [ADX(B)] did not alter preproNPY mRNA content in fed animals, however preproNPY mRNA content in FD animals was increased 2.5-fold. These studies demonstrate that glucocorticoids are necessary and serve a stimulatory role in the increase in hypothalamic preproNPY mRNA levels observed under conditions of FD, and suggest that hypothalamic NPY gene expression may be directly responsive to peripheral metabolic and hormonal signals.

Sustained hyperphagia in adolescent rats that experienced neonatal maternal separation

“…Previous reports have suggested that elevated plasma corticosterone may be necessary for fasting-induced increase in NPY mRNA expression. 20,21 However, in this study, NPY expression in the arcuate nucleus of MS pups was not increased by 24 h food deprivation on PND 29 despite the significant elevation of plasma corticosterone, in contrast to the NH pups showing fasting-induced increases not only of the plasma corticosterone but also of the arcuate NPY. Thus, it is suggested that elevated plasma corticosterone, although it may be necessary, may not be sufficient to increase the arcuate NPY expression during food deprivation.…”

“…It has been suggested that plasma corticosterone is implicated in the hypothalamic NPY expression. [18][19][20][21] Taken together, it is concluded that a chronic increase in plasma corticosterone in MS/RF rats during the repeated fasting/RF cycles might have contributed to a tonic increase in NPY expression, and the increased plasma corticosterone and NPY expression by repeated fasting/RF cycles may partly be in charge of the sustained compensatory hyperphagia in the MS/RF group. Previous reports have suggested that elevated plasma corticosterone may be necessary for fasting-induced increase in NPY mRNA expression.…”

“…[15][16][17] Several results suggest that glucocorticoids regulate the hypothalamic NPY expression: adrenalectomy downregulates the expression of NPY gene in the hypothalamus; 18 NPY neurons in the hypothalamic arcuate nucleus contain glucocorticoid receptors 19 and elevated plasma corticosterone appears to be necessary for fastinginduced increase in NPY mRNA expression. 20,21 These reports led us to hypothesize that neonatal MS may lead to development of eating disorders in the offspring later in life, possibly, due to altered HPA axis characteristics modulating the hypothalamic expression of feeding peptides.…”

The arcuate NPY, POMC, and CART expressions responding to food deprivation are exaggerated in young female rats that experienced neonatal maternal separation

“…An increase in circulating corticosterone and decrease in leptin during food deprivation has been suggested to correlate with fasting-induced changes in the hypothalamic feeding peptides expression. That is, elevated plasma corticosterone was necessary for fasting-induced increase of NPY mRNA expression in mice (Ponsalle et al, 1992;Makimura et al, 2003); the hypothalamic POMC expression has been suggested to be regulated by glucocorticoids (Cintra and Bortolotti, 1992;Savontaus et al, 2002) and leptin (Korner et al, 1999;Schwartz et al, 2000), and the hypothalamic CART by leptin (Kristensen et al, 1998;Lambert et al, 1998). In this study, a 48 h of food deprivation did not significantly increase mRNA level of NPY, nor decrease POMC and CART, in the arcuate nucleus of NH females, despite of a significant increase in the plasma corticosterone and a decrease in leptin.…”

Insulin Inhibits Neuropeptide Y Gene Expression in the Arcuate Nucleus through GABAergic Systems

“…The arcuate nucleus could also be the site for glucocorticoid action, because glucocorticoid receptor (GR) is expressed in the NPY neurons (Hisano et al, 1988), and peripheral as well as central injection of glucocorticoids increased the NPY expression (Wilding et al, 1993;Zakrzewska et al, 1999). More importantly, NPY gene expression was not increased by insulin deficiency if rats were adrenalectomized (Ponsalle et al, 1992;Strack et al, 1995). These data suggest that insulin and glucocorticoids interact with each other to regulate NPY gene expression, although the exact sites of the interaction are not clear.…”