Adrenalectomy reduces neuropeptide Y-induced insulin release and NPY receptor expression in the rat ventromedial hypothalamus.
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Chronic central administration of neuropeptide Y (NPY) causes hyperphagia, hyperinsulinemia, and obesity, a response that is prevented by prior adrenalectomy (ADX) in rats. The basis of NPY's effect and how the acute responses to this peptide are affected by ADX remain unknown. This study investigates the role of glucocorticoids in acute NPY-stimulated food intake, acute NPY-induced insulin release, and hypothalamic NPY-receptor mRNA expression levels. NPY-induced food intake was similar in ADX and control rats after acute intracerebroventricular injection of NPY. Injection of NPY caused a significant increase in plasma insulin in control rats, but this effect was completely absent in ADX rats in which basal plasma insulin levels were also lower than controls. In addition, ADX significantly reduced the number of neurons expressing NPY receptor Y(1) and Y(5) mRNAs in the ventromedial hypothalamus (VMH), without affecting Y(1)- or Y(5)-mRNA expression in the paraventricular hypothalamus or the arcuate nucleus. These data indicate that glucocorticoids are necessary for acute NPY-mediated insulin release and suggest that the mechanisms involve glucocorticoid regulation of Y(1) and Y(5) receptors specifically within the VMH nucleus. (+info)
Corticotropin-releasing hormone links pituitary adrenocorticotropin gene expression and release during adrenal insufficiency.
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Corticotropin-releasing hormone (CRH)-deficient (KO) mice provide a unique system to define the role of CRH in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Despite several manifestations of chronic glucocorticoid insufficiency, basal pituitary proopiomelanocortin (POMC) mRNA, adrenocorticotrophic hormone (ACTH) peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. The normal POMC mRNA content in KO mice is dependent upon residual glucocorticoid secretion, as it increases in both KO and WT mice after adrenalectomy; this increase is reversed by glucocorticoid, but not aldosterone, replacement. However, the normal plasma levels of ACTH in CRH KO mice are not dependent upon residual glucocorticoid secretion, because, after adrenalectomy, these levels do not undergo the normal increase seen in KO mice despite the increase in POMC mRNA content. Administration of CRH restores ACTH secretion to its expected high level in adrenalectomized CRH KO mice. Thus, in adrenal insufficiency, loss of glucocorticoid feedback by itself can increase POMC gene expression in the pituitary; but CRH action is essential for this to result in increased secretion of ACTH. This may explain why, after withdrawal of chronic glucocorticoid treatment, reactivation of CRH secretion is a necessary prerequisite for recovery from suppression of the HPA axis. (+info)
To identify molecular targets of corticosteroid negative feedback effects on neurosecretory neurons comprising the central limb of the hypothalamo-pituitary-adrenal (HPA) axis, we monitored ether stress effects on corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) heteronuclear RNA (hnRNA) expression in rats that were intact or adrenalectomized (ADX) and replaced with corticosterone (B) at constant levels ranging from nil to peak stress concentrations. Under basal conditions, relative levels of both primary transcripts varied inversely as a function of plasma B titers. In response to stress, the kinetics of CRF hnRNA responses of intact and ADX rats replaced with low B were similar, peaking at 5 min after stress. By contrast, intact rats showed a delayed AVP hnRNA response (peak at 2 hr), the timing of which was markedly advanced in ADX/low B-replaced animals (peak at 5-30 min). Transcription factors implicated in these responses responded similarly. Manipulation of B status did not affect the early (5-15 min) phosphorylation of transcription factor cAMP-response element-binding protein (CREB) but accelerated maximal Fos induction from 2 hr after stress (intact) to 1 hr (ADX). Assays of binding by proteins in hypothalamic extracts of similarly manipulated rats toward consensus CRE and AP-1 response elements supported a role for the stress-induced plasma B increment in antagonizing AP-1, but not CRE, binding. These findings suggest that glucocorticoid negative feedback at the transcriptional levels is exerted selectively on AVP gene expression through a mechanism that likely involves glucocorticoid receptor interactions with immediate-early gene products. (+info)
Sympathetic activation of hepatic and splenic IL-1beta mRNA expression during oscillation stress in the rat.
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Interleukin (IL)-1beta mRNA expression in the liver and spleen was examined after subjection to oscillation stress in the rat. Thirty-minute subjection to oscillation stress increased IL-1beta mRNA expression in the both organs. Prior treatment of rats with gadolinium chloride, which eliminates macrophages, prevented the stress-induced IL-1beta expression. Either adrenalectomy or treatment of guanethidine, a blocker of norepinephrine release in the sympathetic nerve endings, partially attenuated the stress-induced response, but the combined treatment completely blocked it. Injection of beta-adrenergic antagonist (propranolol) also suppressed the stress-induced response. These results suggest that oscillation stress induces IL-1beta mRNA expression in the liver and spleen, probably in Kupffer cells and splenic macrophages, and that stress-induced IL-1beta expression is elicited by catecholamines released from sympathetic nerve terminals and the adrenal gland. (+info)
Influence of dietary protein restriction on immune competence. II. Effect on lymphoid tissue.
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Weanling mice fed a 4 percent diet showed a generalized loss of lymphoid tissue which was greater than the loss of total body weight. This effect was greatest in the thymus greater than spleen greater than mesenteric lymph node. Cell loss was most pronounced during the 1st week on diets, then remained at stable levels for 3 weeks and showed a gradual rise thereafter. The effect was shown to be mediated partly by a cessation of growth in lymphoid organs due to the low protein intake and, secondly, an adrenal corticosteroid induced lympholysis which actually reduced cell numbers. Recirculating T cells and resident B cells were amongst the least affected cells whereas stem cells, non-migratory T cells and other reticuloendothelial cells were most depressed in numbers. At no stage was the germinal centre forming capacity of the mesenteric node lost although cell recruitment to antigenically stimulated nodes was diminished. During nutritional repletion the spleen, thymus and mesenteric node all showed different and characteristic regrowth. The spleen was most active initially and rapidly reconstituted haemopoietic cells and B cells. This was followed by the thymus which showed a delayed reinitiation of its normal growth kinetics which had been interrupted by the diet. The evidence suggested that full rehabilitation of the immune apparatus took place even after 2 months of nutritional deprivation. (+info)
Adrenal glucocorticoids modulate [3H]cyclic AMP binding to protein kinase A (PKA), cyclic AMP-dependent PKA activity, and protein levels of selective regulatory and catalytic subunit isoforms of PKA in rat brain.
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Alterations in hypothalamic-pituitary-adrenal (HPA) function are associated with changes in mood and behavior. Protein kinase A (PKA), on activation, phosphorylates many important intracellular proteins and thereby plays a major role in mediating various physiological functions in brain. We systematically examined the relationship of altered HPA function with PKA modifications in rat brain after administering corticosterone to normal rats and by first adrenalectomizing rats and then simultaneously treating them with different doses of corticosterone. Rats were decapitated on day 1, 4, or 14. Subcutaneously implanted 50- or 100-mg corticosterone pellets in normal rats for 4 or 14 days significantly decreased PKA activity, B(max) of [3H]cyclic AMP binding, and protein levels of selective PKA regulatory (RIalpha, RIIbeta) and catalytic (Catbeta) subunit isoforms in cortex and hippocampus in a dose-dependent manner without any significant changes at day 1; these changes were more pronounced at day 14. However, adrenalectomy caused the opposite changes in these measures at day 4 or 14 in both cortex and hippocampus, and the magnitude of the changes was more pronounced at day 14. Simultaneous treatment with implanted corticosterone at 50- or 100-mg doses in adrenalectomized rats reversed the adrenalectomy-induced increases in PKA measures in a dose-dependent manner. These results suggest that endogenous glucocorticoid modifies the expression of RIalpha, RIIalpha, and Catbeta subunit isoforms of PKA, as well as the catalytic and regulatory activities of PKA, and that these alterations in PKA may in part explain HPA axis-mediated changes in mood and behavior. (+info)
Evidence for activation of the tissue kallikrein-kinin system in nociceptive transmission and inflammatory responses of mice using a specific enzyme inhibitor.
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The pharmacological activity of phenylacetyl-Phe-Ser-Arg-N-(2, 4-dinitrophenyl)-ethylenediamine (TKI), a tissue kallikrein specific inhibitor, was assessed using models of nociception and inflammation in mice. Injection of TKI (13.6 - 136 micromol kg(-1), i.p. or 41 - 410 micromol kg(-1), s.c.) produced a dose-related inhibition of the acetic acid-induced writhes (by 37 to 85% or 34 to 80%, respectively). The antinociceptive activity of TKI (41 micromol kg(-1), i.p.) was maximal after 30 min injection and lasted for 120 min. The effect was unaltered by pretreatment with naloxone (8.2 micromol kg(-1), s.c.) or bilateral adrenalectomy. TKI (41 and 136 micromol kg(-1), i.p.) produced a dose-related decrease of the late phase of formalin-induced nociception by 79 and 98%, respectively. At 136 micromol kg(-1), i.p., TKI also shortened the duration of paw licking in the early phase by 69%. TKI (41 and 136 micromol kg(-1), i.p.) also reduced the capsaicin-induced nociceptive response (by 51 to 79%). TKI (41 micromol kg(-1), i.p. or 410 micromol kg(-1), s.c.) reduced the oedematogenic response, from the second to the fifth hour after carrageenin injection by 36 to 30% or by 47 to 39%, respectively. Pretreatment with TKI (41 micromol kg(-1), i.p.) reduced the capsaicin-induced neurogenic inflammation in the mouse ear by 54%. It is concluded that TKI presents antinociceptive and antiinflammatory activities mediated by inhibition of kinin formation by tissue kallikrein in mice. The results also indicate that the tissue kallikrein-dependent pathway contributes to kinin generation in nociceptive and inflammatory processes in mice. (+info)
p53 accumulation due to down-regulation of ubiquitin: relevance for neuronal apoptosis.
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The p53 tumor suppressor protein is a major regulator of cell growth arrest and apoptosis in response to DNA damage. Both p53 function and stability are tightly controlled by Mdm2, which binds to the p53 N-terminus and targets p53 for ubiquitin-mediated proteolysis. Previous studies suggest that adrenalectomy-induced neuronal apoptosis is p53-dependent. Here we demonstrate both nuclear accumulation and functional activation of p53 protein in apoptotic hippocampal neurons from adrenalectomized rats. Increased p53 expression occurred despite the accumulation of its negative regulator, Mdm2, and the formation of p53-Mdm2 complexes. The persistence of p53 expression was explained by a striking decrease in free ubiquitin in p53-positive neurons. The addition of exogenous ubiquitin to p53-Mdm2 complexes from apoptotic neurons restored p53 degradation. These findings demonstrate a novel mechanism of p53 stabilization mediated by decreased ubiquitin levels. Regulation of free ubiquitin may therefore be an effective way to modulate p53-dependent apoptosis in certain cell types. (+info)