Biomedical subjects

E Spinedi

Publications and source records attributed to E Spinedi.

At least 19 recordsLinked to original sources

PubMed2006

Impact of transient correction of increased adrenocortical activity in hypothalamo-damaged, hyperadipose female rats.

OBJECTIVE: To explore the effects of transient correction of enhanced corticoadrenal activity in monosodium L-glutamate (MSG)-damaged female rats on peripheral insulin sensitivity and in vitro retroperitoneal (RP) adipocyte function. DESIGNS: A dose of 4 mg/g body weight (BW) of MSG or vehicle (CTR) was i.p. injected, once every 2 days, between days 2 and 10 of age, in female rats. Intact and 21 day-operated (sham or adrenal enucleation (AE)) rats from both (CTR and MSG) groups were used for experimentation on day 120 of age. Circulating levels of several hormones, in basal and after i.v. high-glucose load conditions, and RP adiposity morphology and function were then evaluated. RESULTS: MSG rats developed increased adrenocortical function, hyperadiposity, hyperleptinemia, hyperinsulinemia and decreased peripheral insulin sensitivity. These characteristics were fully reversed after transient correction of corticoadrenal hyperactivity induced by AE. In addition, in vitro experimentation with isolated RP adipocytes indicated that cells from intact MSG animals displayed decreased sensitivity to insulin and dexamethasone stimulation of leptin secretion. Interestingly, adipocyte dysfunction in MSG rats was fully abrogated after AE-induced transient correction of insulinemia, leptinemia and adrenocortical activity. Importantly, the reversion of these metabolic abnormalities, induced by AE for 21 days, in MSG animals did occur, despite no significant changes in BW values. CONCLUSION: Our results support that the changes in adipocyte characteristics and peripheral insulin resistance, developed in this pseudo-obese female rat model, are mainly due to increased glucocorticoid production. Importantly, appropriate correction of the enhanced adrenocortical activity fully reversed these abnormal functions.

Adipocytes↗

PubMed2005

Testis structure and function in a nongenetic hyperadipose rat model at prepubertal and adult ages.

There are few data for hormonal levels and testis structure and function during postnatal development in rats neonatally treated with monosodium L-glutamate (MSG). In our study, newborn male pups were ip injected with MSG (4 mg/g body weight) every 2 d up to 10 d of age and investigated at prepubertal and adult ages. Plasma levels of leptin, LH, FSH, prolactin, testosterone (T), corticosterone, and free T4 (FT4) were measured. MSG rats displayed elevated circulating levels of corticosterone and hyperadiposity/hyperleptinemia, regardless of the age examined; conversely, circulating prolactin levels were not affected. Moreover, prepubertal MSG rats revealed a significant (P < 0.05) reduction in testis weight and the number of Sertoli (SC) and Leydig cells per testis. Leptin plasma levels were severalfold higher (2.41 vs. 8.07; P < 0.05) in prepubertal MSG rats, and these animals displayed plasma LH, FSH, T, and FT4 levels significantly decreased (P < 0.05). Taken together, these data indicate that testis development, as well as SC and Leydig cell proliferation, were disturbed in prepubertal MSG rats. Adult MSG rats also displayed significantly higher leptin plasma levels (7.26 vs. 27.04; P < 0.05) and lower (P < 0.05) LH and FSH plasma levels. However, T and FT4 plasma levels were normal, and no apparent alterations were observed in testis structure of MSG rats. Only the number of SCs per testis was significantly (P < 0.05) reduced in the adult MSG rats. In conclusion, although early installed hyperadipose/hyperleptinemia phenotype was probably responsible for the reproductive axis damages in MSG animals, it remains to be investigated whether this condition is the main factor for hypothalamus-pituitary-gonadal axis dysfunction in MSG rats.

Adipose Tissue↗

PubMed2001

Impact of maternal undernutrition on hypothalamo-pituitary-adrenal axis and adipocyte functions in male rat offspring.

Malnutrition induces profound deleterious effects on several metabolic and neuroendocrine functions. In the present study, we examined the impact of maternal food restriction, during gestation and lactation, on the metabolic-neuroendocrine function of their male offspring at 21 and 60 d of age. Well-nourished (WN) and undernourished (UN) pregnant rats were used, during gestation and lactation, until pups were weaned. Twenty-one-day-old WN and UN male pups were studied in basal and postinsulin conditions. Additional groups of weaned (WN and UN) male rats were fed either ad libitum (WN-WN and UN-WN) or in a restricted fashion (WN-UN and UN-UN) until experimentation at age 60 d. Body weights of mothers and their male offspring were monitored. Basal and postinsulin plasma concentrations of several metabolic fuels were evaluated. Our results indicate that 21-d-old UN male rats exhibited (vs their WN counterparts), decreased body weights, similar basal and postinsulin glycemia, similar basal plasma adrenocorticotropic hormone (ACTH) and corticosterone levels but diminished ACTH response to insulin treatment, and basal hypoleptinemia and significant insulin-induced leptin release. Finally, at 60 d of age, long-term UN (WN-UN and UN-UN) rats showed lower plasma (basal and postinsulin) glucose, and basal triglyceride levels than their counterparts (WN-WN and UN-WN). Sixty-day-old rats submitted to either food restriction protocol also showed a reduced hypothalamo-pituitary-adrenal axis response to insulin-induced hypoglycemia and basal hypoleptinemia, in spite of restoration of normal body weights. These results further indicate a clear metabolic-neuroendocrine dysfunction in male pups of UN mothers, with the abnormality partially present at weaning and deteriorated by adulthood, even after the recovery of normal body weight. Our study strongly supports the importance of the irreversibility of a deleterious allostatic state resulting from fetal and early postnatal undernutrition.

Adipocytes↗

PubMed2000

Cytokines, leptin, and the hypothalamo-pituitary-adrenal axis.

The endocrine and immune systems are linked via an elaborated communication system constituted by an array of cytokines and neuropeptides which interact to modulate the integrated response of an organism to infection. Weight loss and anorexia, probably secondary to cytokine release, frequently accompany infection, but leptin could also play a role. Like cytokines, leptin serves as a peripheral messenger to convey signals to the brain. Expression of leptin is stimulated by glucocorticoids, endotoxins, and cytokines; on the other hand, leptin seems to inhibit the activation of the hypothalmo-pituitary-adrenal (HPA) axis. Indeed leptin exerts a direct, dose-dependent inhibition of stimulated cortisol secretion by normal human and rat adrenal cells in vitro. These effects are mediated by the long isoform of the leptin receptor, because its transcript is expressed in the adrenal tissue. In addition we investigated the role played by the glucocorticoids in the development of tolerance of the hypothalamo-corticotropic, immune and adipose system responses to repeated endotoxin administration. Unlike that of the corticotropic axis, tolerance of the immune and adipose systems is at least partially glucocorticoid-independent. This crosstalk between the endocrine, immune, and adipose systems may be of prime importance to homeostasis in pathophysiological events occurring during infection.

Animals↗

PubMed2000

Metabolic, neuroendocrine and immune functions in basal conditions and during the acute-phase response to endotoxic shock in undernourished rats.

Chronic malnutrition is one of the most important causes of several metabolic, immune and neuroendocrine dysfunctions. The aim of the present study was to determine the influence of chronic food restriction on basal neuroendocrine, immune and adipocyte functions and during the acute-phase response to endotoxic shock in female rats. The effect of refeeding of undernourished rats on the above-mentioned functions was also investigated. For these purposes, plasma total protein, glucose, triglycerides, ACTH, corticosterone, tumor necrosis factor-alpha (TNF) and leptin (LEP) levels were determined in basal condition and 2 h after endotoxin (LPS; 180 microgram/kg body weight, i.p.) administration in 3 different groups: (1) well-nourished (WN) controls; (2) undernourished (UN) rats as a consequence of chronic food restriction, and (3) UN rats re-fed to restoration of their body weights in the WN rat range. The results indicate that UN rats, in comparison with WN controls, developed an arrest in body weight gain as well as in basal hypoglycemia, hypotriglyceridemia, hypoleptinemia, hypercorticosteronemia and enhanced adrenal glucocorticoid content; however, no changes in basal total protein, ACTH and TNF plasma levels and in anterior pituitary ACTH concentrations were found. When endotoxic shock was induced, the LPS-induced hypoglycemia developed in WN rats was abolished in UN animals, and both ACTH and TNF plasma concentrations after endotoxin, albeit significantly (p < 0.05) higher than the respective basal values, were significantly (p < 0.05) lower in UN than in WN control rats. Despite the high basal plasma corticosterone concentration in UN vs. WN rats, the LPS-induced glucocorticoid release was similar in WN and UN rats. Additionally, LPS treatment did not modify basal plasma LEP levels, regardless of the group. Interestingly, UN rats fed ad libitum for 15 days restored their body weight to WN rat range values, and the various metabolic dysfunctions seen in UN rats in both basal and post-LPS conditions were fully normalized. Our results clearly indicate that chronic undernutrition not only affects, as earlier described, reproductive function but also metabolic, neuroendocrine, immune and adipocyte functions, and that the effects induced by undernutrition can be fully reversed after recovery of normal body weight. The present study strongly supports the involvement of the metabolic status in the effectiveness of the defense mechanisms developed in patients in inflammatory stress conditions.

Acute-Phase Reaction↗

PubMed2000

Modulatory role of the epinergic system in the neuroendocrine-immune system function.

It is well recognized that the reciprocal interaction established between the immune and neuroendocrine systems is crucial for the homeostatic adaptation of individuals during septicemia. In the present study, using an in vivo rat model, we investigated the degree of participation of central and peripheral epinergic systems in the modulation of the hypothalamic-pituitary-adrenal and immune axes' functions during endotoxemia. For this purpose, acute endotoxemia was induced in adult male rats pretreated intraperitoneally with either different inhibitors of phenylethanolamine-N-methyltransferase (PNMT) [which are active either peripherally (SKF 29661) or both peripherally and centrally (SKF 64139), thus lowering epinephrine (EPI) synthesis] or vehicle only (CTRL). Twelve hours after pretreatment, animals were intraperitoneally injected with vehicle alone (basal) or vehicle containing bacterial lipopolysaccharide (LPS) and sacrificed 2 h later. A significant (p < 0.05 vs. the respective basal value) hypoglycemia was found in all groups studied. No pretreatment modified basal plasma adrenocorticotropic hormone (ACTH), glucocorticoid and cytokine concentrations. Endotoxin-stimulated ACTH secretion was severalfold (p < 0.05) higher than the respective basal value in CTRL and in SKFs-pretreated rats; however, the plasma ACTH levels after LPS were significantly (p < 0.05 vs. CTRL and SKF-29661 values) reduced in SKF-64139-pretreated rats. All groups studied showed an appropriate adrenal response to endotoxin challenge. Although no differences were found in basal anterior pituitary (AP) ACTH content among groups, LPS treatment significantly (p < 0.05 versus the respective basal value) decreased AP ACTH in CTRL and SKF 29661 groups. No pretreatment modified the basal medial basal hypothalamus (MBH) corticotropin-releasing hormone (CRH) content. Conversely, SKF 64139 pretreatment significantly (p < 0.05 vs. CTRL and SKF 29661 values) reduced basal median eminence (ME) CRH content, and LPS administration significantly (p < 0.05) decreased ME CRH in CTRL and SKF-29661-pretreated rats. SKF 64139 pretreatment significantly (p < 0.05) enhanced basal MBH and ME arginine vasopressin (AVP) contents. LPS administration significantly (p < 0.05) decreased MBH AVP in CTRL and SKF-29661-pretreated rats and diminished (p < 0.05 vs. basal values) ME AVP in all groups. The plasma tumor necrosis factor alpha (TNFalpha) concentrations were enhanced severalfold (p < 0.05 vs. basal values) after LPS treatment in CTRL rats, but not in SKFs-treated animals. In order to explore the reduced cytokine release after LPS in PNMT-inhibited rats, additional ex vivo experiments were performed by using peripheral mononuclear cells (PMNC) from both CTRL and SKF-29661-pretreated rats. The results of these experiments confirmed an immune dysfunction after inhibition of peripheral EPI synthesis; in fact, basal and concanavalin-A-stimulated TNFalpha secretions were significantly (p < 0.05) lower in SKF-29661-treated than in CTRL PMNC, while, interestingly, addition of EPI (10(-7) M) to the medium fully restored these effects. These data demonstrate that: (1) the mechanism whereby LPS-induced hypoglycemia was independent of epinergic activity; (2) selective central inhibition of epinergic function reduced endotoxin-stimulated ACTH secretion, an effect that could mainly be due to a decrease in CRH-ergic activity; (3) the central epinergic system positively and negatively modulates CRH- and AVPergic functions, respectively, and (4) inhibition of peripheral PNMT activity reduced immune system function in vivo and ex vivo. It is further suggested that low peripheral levels of EPI could be beneficial for the body's defense mechanisms during endotoxic shock.

Acute-Phase Reaction↗

PubMed2000

Food intake-induced leptin secretion modulates hypothalamo-pituitary-adrenal axis response and hypothalamic Ob-Rb expression to insulin administration.

The mutation of the ob gene is known to induce a phenotype of obesity accompanied by symptoms including enhanced production of glucocorticoid. Chronic administration to ob/ob mice of leptin, the ob gene product, reverses hypercorticosteronemia. This establishes a clear relation between adipocyte and hypothalamo-pituitary-adrenal (HPA) axis functions. In the present study we investigated the acute modulatory effects of food intake-stimulated leptin secretion on HPA axis activity and hypothalamic leptin receptor (Ob-Rb) expression in 24-hour fasting, adult female, BALB/c mice after insulin-induced hypoglycemia. Our results indicate that: (1) food supply for 45 min to 24-hour fasting mice increased plasma glucose levels and reversed both hypercorticosteronemia and hypoleptinemia; (2) the insulin-induced hypoglycemia produced a marked HPA axis activation in animals with no access to food but this response was fully prevented by food intake and the consecutive increase in plasma leptin levels; (3) the inhibitory effect of leptin on the HPA axis response to insulin-induced hypoglycemia was corroborated by i.p. administration of murine leptin, and (4) fasting-induced hypothalamic Ob-Rb overexpression is not modulated by insulin itself but by leptin, since increase in leptin levels by food intake or by administration of exogenous leptin completely reversed this Ob-Rb overexpression. These results confirm the inhibitory effect of leptin on the HPA axis response to various stress stimuli. They clearly demonstrate that acute food intake in 24-hour fasting mice: (a) rapidly reduced fasting-induced hypercorticosteronemia by enhancing both spontaneous and insulin-elicited endogenous leptin secretion; (b) fully prevented HPA axis response to insulin administration, by rapidly increasing endogenous leptin secretion and probably also by diminishing the extent and the duration of insulin-induced hypoglycemia, and (c) abolished hypothalamic Ob-Rb overexpression induced by fasting itself combined with insulin treatment. The present data strongly suggests an inhibitory effect of endogenous leptin on insulin-induced HPA axis response, an interaction relevant to the physiological adaptation to starvation and caloric excess, and further supports the pivotal role played by the hypothalamus in restoring homeostasis in different allostatic states.

Adrenocorticotropic Hormone↗

PubMed2000

Circulating and mitogen-induced tumor necrosis factor (TNF) in malnourished children.

Malnutrition in children is associated with an increased risk of infection and death. Multiple abnormalities in the inflammatory-immune response, including cytokine production, have been described in protein energy malnourished (PEM) children and could account for increased severity and frequency of infection. The aim of the present study was to determine whether there are abnormal basal tumor necrosis factor (TNF) serum concentrations in PEM children, to relate it with serum cortisol and plasma corticotrophin levels and to explore simultaneously the in vitro production of TNF by peripheral blood leukocytes (PBL). No differences were found in basal plasma corticotrophin and serum cortisol concentrations in malnourished as compared with normal, well-nourished control children. Basal TNF serum concentrations were significantly higher in malnourished children than in controls. Conversely, mitogen induced TNF production by PBL in vitro was significantly reduced in PEM children compared with controls. Abnormalities in circulating and mitogen-induced TNF production are present in malnourished children even in absence of elevated serum cortisol concentrations. These abnormalities potentially could modify inflammatory-immune responses to infectious stimuli in malnourished children.

Adrenocorticotropic Hormone↗

PubMed1999

Role of glucocorticoids in the response of the hypothalamo-corticotrope, immune and adipose systems to repeated endotoxin administration.

The present study was designed to determine whether the glucocorticoid inhibitory feedback mechanism plays a role in the well-known tolerance of the neuroendocrine-immune axis response to repeated endotoxemia. Adult male rats underwent adrenalectomy (ADX) and were implanted with a subcutaneous corticosterone (compound B, CB, 75 mg) pellet, or sham operated and implanted with a placebo pellet. On the morning of day 8 after surgery (experimental day, D1), all rats received an intravenous injection of lipopolysaccharide (LPS) (25 microg/kg body weight) which was repeated daily until D5. Blood was drawn via intravenous indwelling catheters before (sample time zero) as well as 1, 2, 3 and 4 h after LPS treatment on D1, 3 and 5 for measurements of corticotropin (ACTH), CB, tumor necrosis factor-alpha (TNF-alpha) and leptin. In sham animals, tolerance to repeated LPS administration was complete by D5 for the corticotrope axis and the immune response. In addition, LPS was found to stimulate leptin secretion on day 1 in intact rats, an effect that also disappeared thereafter. ADX + CB rats showed only a partial tolerance of the corticotrope axis on D5, whereas tolerance of the immune response was similar to that found in sham animals. Interestingly, the acute stimulation of leptin secretion by LPS in ADX + CB rats was qualitatively similar to that of intact controls on D1, but plasma leptin levels were significantly reduced on D3 and 5 compared to controls. Our results demonstrate that the adrenal response tolerance of the hypothalamo-pituitary-adrenal axis to repeated endotoxemia. In addition, our finding that TNF-alpha secretion follows the same pattern in sham-operated and in adrenalectomized animals suggests that unlike the corticotrope axis, tolerance of the immune response does not depend upon stimulated CB levels. The decrease in circulating levels of leptin following ADX is consistent with the stimulatory effects of glucocorticoids on leptin secretion. However, our finding of an acute stimulation of leptin secretion by LPS in ADX + CB animals demonstrates that this effect of endotoxemia is at least partially glucocorticoid independent.

Adipose Tissue↗

PubMed1998

The hypothalamo-pituitary-adrenal axis of athymic Swiss nude mice. The implications of T lymphocytes in the ACTH release from immune cells.

Because of the well-known role of the thymus in the regulation of immune function, we investigated whether the lack of thymus may affect hypothalamo-pituitary-adrenal (HPA) axis activity. Eight-week-old female Swiss nude (athymic) and BALB/c (normal) mice were used to study (a) the "in vivo" response of the HPA axis to various stresses and stimuli acting at either hypothalamic, pituitary, or adrenal levels and (b) the "in vitro" response of pituitary and adrenal cells to CRH and ACTH stimulation, respectively. The results indicate that (1) basal plasma ACTH levels were significantly (p < 0.05) higher in Swiss nude than in BALB/c mice, whereas basal corticosterone (B) levels were similar in both strains of mice; (2) the stress-induced release of ACTH and B in plasma was significantly (p < 0.05) lower in Swiss nude than in BALB/c mice, regardless of the stimulus applied; (3) the "in vitro" pituitary response to CRH and the adrenal response to ACTH were significantly (p < 0.05) lower in Swiss nude than in BALB/c mice; and (4) whereas hypothalamic CRH and pituitary ACTH contents were similar in both strains, adrenal B content was significantly (p < 0.05) lower in athymic mice. Immune reconstitution of the athymic nude mice by injecting splenocytes obtained from syngeneic heterozygous (i.e., immunologically fully competent) donors produced a significant increase in the B adrenal content of the nude mice. Among the splenocytes, CD4+ T-lymphocytes play a particularly important role in the release of ACTH from cells of the immune system. In conclusion, our results indicate that athymic nude mice have a blunted HPA axis response to various stresses and stimuli; this defect seems to reside at both the pituitary and adrenal levels. Immune reconstitution of the nude mice leads to a normalization of the adrenal B content.

Adrenal Glands↗

PubMed1998

Gender-dependent characteristics of the hypothalamo-corticotrope axis function in glucocorticoid-replete and glucocorticoid-depleted rats.

The aim of the present study was to determine the role of the endogenous sex steroid environment in the hypothalamo-corticotrope (HC) function in both sham-operated (SHAM) and bilaterally adrenalectomized (ADX) rats. For this purpose adult rats of both sexes were used 3 and 6 weeks after either SHAM or ADX. The results indicate that: a) in SHAM animals, basal plasma ACTH levels were significantly higher in females than in males, and this sexual dimorphism was overridden by ADX, regardless of the time post-surgery; b) although basal anterior pituitary (AP) ACTH content was similar in SHAM animals of both sexes, 3- and 6-week ADX induced higher AP ACTH in males than in females; c) at 3- and 6-weeks, ADX rats of hoth sexes had an AVP:CRH ratio (r), in the median eminence (ME) and medial basal hypothalamus (MBH), increased several fold over the respective SHAM-value and, although no sexual dimorphism was found at week 3 post-ADX, by 6-weeks post ADX, these ratios were significantly higher in both brain tissues of females than in those of males; and d) the in vitro ME CRH and AVP output in response to high potassium concentrations (hK+; 28 and 56 mmol/I), was concentration-related, regardless of sex and surgery, and was characterized by enhanced secretion of neuropeptides by MEs from ADX in comparison to SHAM rats of both sexes, and a sexual dimorphism was found in this parameter, consisting in general, in greater neuropeptide output from tissues of female than of male animals. Our results indicate that: 1) there is a gender-dependent characteristic of the HC axis function in glucocorticoid-replete rats and 2) the absence of the glucocorticoid negative feedback mechanism is responsible for either the expression or for the override of the sexual dimorphism in different parameters, a phenomenon which dependent on the time elapsed after ADX.

Adrenal Cortex↗

PubMed1998

Sex- and stress-steroids interactions and the immune system: evidence for a neuroendocrine-immunological sexual dimorphism.

It is well established that sexual dimorphism exits within the immune system. Females have higher levels of immunoglobulins, greater antibody response to antigens, and higher incidence of autoimmune diseases, such as systemic lupus erythematosus, Grave's disease, and Hashimoto thyroiditis than males. Spontaneous autoimmune syndromes in mice are more prevalent and of greater severity in females compared with males, and the course of the disease can be modulated by changes in levels of gonadal steroids. A sexual dimorphism is also present in the pituitary-adrenal function: females have higher corticosterone levels and higher corticosteroidogenesis. In the context of the immune-neuroendocrine interactions, we investigated the effects of gonadectomy and sex hormone therapy on endotoxin-stimulated hypothalamo-pituitary-adrenal axis. Whereas endotoxin-induced corticosterone release is invariable throughout the different stages of the oestrus cycle, gonadectomy in both male and female mice leads to enhanced adrenal and immune responses to endotoxin. Interestingly, these enhanced adrenal and immune responses can be completely reversed by testosterone treatment regardless of the sex of the mice. Studies performed over development confirm the role of endogenous testosterone in modulating the endotoxin-induced corticosterone secretion. Indeed, corticosterone response to endotoxin is maximal before puberty when endogenous testosterone levels are low and declines in postpubertal and adult mice. In conclusion, all these data support a sex steroid hormone basis for a neuroendocrine-immunologic sexual dimorphism.

Animals↗

PubMed1998

A phospholipase A2-related snake venom (from Crotalus durissus terrificus) stimulates neuroendocrine and immune functions: determination of different sites of action.

Immune neuroendocrine interactions are vital for the individual's survival in certain physiopathological conditions, such as sepsis and tissular injury. It is known that several animal venoms, such as those from different snakes, are potent neurotoxic compounds and that their main component is a specific phospholipase A type 2 (PLA2). It has been described recently that the venom from Crotalus durissus terrificus [snake venom (SV), in the present study] possesses some cytotoxic effect in different in vitro and in vivo animal models. In the present study, we investigated whether SV and its main component, PLA2 (obtained from the same source), are able to stimulate both immune and neuroendocrine functions in mice, thus characterizing this type of neurotoxic shock. For this purpose, several in vivo and in vitro designs were used to further determine the sites of action of SV-PLA2 on the hypothalamo-pituitary-adrenal (HPA) axis function and on the release of the pathognomonic cytokine, tumor necrosis factor alpha (TNF alpha), of different types of inflammatory stress. Our results indicate that SV (25 microg/animal) and PLA2 (5 microg/animal), from the same origin, stimulate the HPA and immune axes when administered (i.p.) to adult mice; both preparations were able to enhance plasma glucose, ACTH, corticosterone (B), and TNF alpha plasma levels in a time-related fashion. SV was found to activate CRH- and arginine vasopressin-ergic functions in vivo and, in vitro, SV and PLA2 induced a concentration-related (0.05-10 microg/ml) effect on the release of both neuropeptides. SV also was effective in changing anterior pituitary ACTH and adrenal B contents, also in a time-dependent fashion. Direct effects of SV and PLA2 on anterior pituitary ACTH secretion also were found to function in a concentration-related fashion (0.001-1 microg/ml), and the direct corticotropin-releasing activity of PLA2 was additive to those of CRH and arginine vasopressin; the corticotropin-releasing activity of both SV and PLA2 were partially reversed by the specific PLA2 inhibitor, manoalide. On the other hand, neither preparation was able to directly modify spontaneous and ACTH-stimulated adrenal B output. The stimulatory effect of SV and PLA2 on in vivo TNF alpha release was confirmed by in vitro experiments on peripheral mononuclear cells; in fact, both PLA2 (0.001-1 microg/ml) and SV (0.1-10 microg/ml), as well as concavalin A (1-100 microg/ml), were able to stimulate TNF alpha output in the incubation medium. Our results clearly indicate that PLA2-dependent mechanisms are responsible for several symptoms of inflammatory stress induced during neurotoxemia. In fact, we found that this particular PLA2-related SV is able to stimulate both HPA axis and immune functions during the acute phase response of the inflammatory processes.

Adrenal Glands↗

PubMed1998

A regulatory loop between the hypothalamo-pituitary-adrenal (HPA) axis and circulating leptin: a physiological role of ACTH.

The product of the ob/ob gene, leptin, is known to be able to exert a modulator, role on HPA axis function. The aim of the present study was to determine whether endogenous ACTH and glucocorticoids exert any regulatory effect on leptin secretion. For this purpose bilaterally adrenalectomized (ADX) or sham operated (Sham) adult male rats were implanted with an indwelling i.v. catheter. A subgroup of ADX animals received, at the same time of surgery, a s.c. corticosterone (B) pellet (75 mg) (ADX+B). All animals were subjected to experimental designs 7 days after surgery. Our results indicate, as expected, that 7-day ADX animals have several fold increased basal ACTH plasma levels and non detectable circulating B, whereas ADX+B rats showed basal plasma ACTH levels in the range of Sham values and plasma B concentrations of about 5 microg/dl. Interestingly, basal plasma leptin levels were significantly (P < 0.05) decreased by 7 days post ADX, and B replacement therapy (ADX+B) restored circulating leptin to Sham levels. Acute dexamethasone (Dxmn, 30 microg/kg body weight, i.v.) treatment induced a very rapid decrease in plasma ACTH concentrations in both Sham and ADX rats, as well as a decrease in plasma B levels in Sham rats. Interestingly, Dxm test had no effect on plasma leptin levels in Sham animals; however, in ADX rats, the synthetic glucocorticoid increased plasma leptin concentrations, restoring the levels observed in Sham rats. This effect occurred at the same time when plasma ACTH levels were decreasing toward basal Sham values. These results clearly indicate that, beside the known effects of leptin on HPA axis function, circulating ACTH and glucocorticoid are able to modulate leptin secretion in plasma. The lack of circulating glucocorticoid and/or increased plasma ACTH concentrations, are responsible for decreasing leptin output, whereas decreased plasma ACTH concentrations allow an increase of leptin secretion in blood. Our data strongly support the existence of a closed, bi-directional, circuit between HPA axis function and adipose tissue metabolism. They further indicate the physiological relevance of different types of stress associated with many phenotypes of obesity.

Adrenalectomy↗

PubMed1997

Bilateral adrenal enucleation-induced changes in adenohypophyseal pro-opiomelanocortin (POMC)-related peptides synthesis and secretion: a comparative study with adrenalectomized rats.

The aim of the present study was to elucidate the modulatory effect of transient changes in endogenous glucocorticoids, occurring after bilateral adrenal enucleation (ENUC), on anterior pituitary (AP) proopiomelanocortin (POMC)-derived peptides synthesis and output in rats. For this purpose, adult female rats were either bilaterally ENUC, adrenalectomized (ADX), or sham-operated (SHAM) and killed by decapitation 2, 7, 14, and 21 days after surgery. Trunk blood was collected for measurements of ACTH, beta-endorphin (beta-END) and corticosterone (B) concentrations; APs were quickly dissected for the determination of ACTH, beta-endorphin (beta-END)-like (beta-END-LI) and gamma 3-MSH contents and adrenal glands were removed and submitted to histological study. The results indicate that ENUC and ADX increased AP POMC-related peptides synthesis and release in association with changes in the AP processing of peptides belonging to the N-terminal (gamma 3-MSH), mid (ACTH) and C-terminal (beta-LPH/ENDs) portions of POMC. While ADX abolished plasma B levels, ENUC induced a transient (day 2) decrease in plasma B concentrations which returned to SHAM levels at 7 days after surgery. These data tallied with the histological observations carried out, indicating a time-dependent regenerative process of the adrenal which was completed by three weeks after ENUC. There was a different pattern in plasma ACTH and beta-END levels between ENUC and ADX; maximal plasma peptide levels were found 7-14 days after ENUC, then falling down to SHAM values at 21 days post ENUC. Conversely, there was a constant increment in plasma peptide levels up to 21 days after ADX. At 2 days after both ENUC and ADX all peptides measured in the AP were lower than SHAM values, thus reflecting a rapid corticotrope secretion. Thereafter, 7 or more days after surgery, AP peptide content in ADX rats increased, in a time-related fashion, up to 21 days after surgery. Only beta-END-LI showed a similar AP content to that of the SHAM group, thereafter indicating a preferential cleavage of POMC to beta-END long after ADX (21 days). ENUC rats showed increased AP POMC peptides content throughout the whole time, and it was significantly different from SHAM and ADX values 14 days post-surgery. Interestingly, we found an increment in AP gamma 3-MSH, a peptide which is preferentially synthesized in the intermediate lobe of the rat pituitary, in both ENUC and ADX situations. Our results further indicate that: 1) glucocorticoids, from regenerating adrenal origin, induce a fast negative feedback mechanism on AP secretion, and 2) there might be a delayed inhibitory action of newly synthesized corticosteroids on higher levels of the central nervous system. The lack of glucocorticoids (ADX) clearly corroborates a persistent enhancement of AP POMC-related peptides synthesis and secretion. The differences in AP processing of POMC between ENUC and ADX might be due to qualitative/quantitative changes in hypothalamic ACTH secretagogues output.

Adrenal Glands↗

PubMed1997

Increased vasopressinergic activity as a possible compensatory mechanism for a normal hypothalamic-pituitary-adrenal axis response to stress in BALB/c nude mice.

A bidirectional relationship between the immune and neuroendocrine systems is now widely accepted. Since it is well known that the thymus plays an important role in the regulation of the immune function, we decided to explore whether a lack of the thymic function may influence hypothalamic-pituitary-adrenal (HPA) axis activity. Eight-week-old female mice of both strains, nude and control BALB/c, were used to study: (a) the in vivo response of the HPA axis to several stress stimuli acting at either the hypothalamic (insulin administration and ether vapor inhalation), pituitary (CRH and vasopressin injections) or adrenal (ACTH treatment) level and (b) the in vitro response of hypothalamic fragments to high KCl (48 mM) stimulation. The results indicate that: (1) basal plasma ACTH and vasopressin levels were significantly (p < 0.05) higher in nude than in control BALB/c mice, whereas basal plasma corticosterone concentrations were similar in both strains of mice; (2) although no significant strain-related difference in the stress-induced ACTH secretion in plasma was found, hypothalamic stimuli were able to induce a significantly (p < 0.05) higher secretion of glucocorticoid in plasma in nude than in control BALB/c mice; (3) the pattern of in vitro hypothalamic CRH release was similar in both strains of animals; however, basal AVP output and that stimulated by 48 mM KCl were significantly (p < 0.05) higher in nude than in control hypothalamic fragments, and (4) whereas hypothalamic CRH, pituitary ACTH and adrenal glucocorticoid contents were similar in both strains, hypothalamic AVP content was significantly (p < 0.05) higher in athymic than in control mice. In summary, our results indicate that nude mice have an increased vasopressinergic function which could contribute to a normal HPA axis activity; thus, adult athymic mice of BALB/c origin could compensate, due to their increased vasopressinergic function, for a robust glucocorticoid release to protect themselves immediately after aggression. It remains to be determined whether this enhanced vasopressinergic function is a result of an early adrenal insufficiency due to congenital deficiency of thymic factors known to stimulate HPA axis function.

Adrenocorticotropic Hormone↗

PubMed1997

Participation of the central serotonergic pathway in the endotoxin-stimulated hypothalamo-pituitary-adrenal axis function.

The aim of the present study was to determine whether the central serotoninergic pathway (5HT) plays any stimulatory/inhibitory role in endotoxin-stimulated hypothalamo-pituitary-adrenal (HPA) axis function in the male rat. For this purpose, animals inhibited or not of central 5HT synthesis were injected with vehicle alone or containing endotoxin (LPS) and killed 2 h later. The results indicate that the inhibition of the 5HT pathway did not modify the LPS-induced hypoglycemia but that it significantly reduced ACTH release in plasma. Although the inhibition of 5HT did not modify the CRH-ergic system, it diminished hypothalamic vasopressin (AVP) content in basal condition. After LPS injection, rats inhibited of 5HT synthesis showed a significant activation of the hypothalamic AVP-ergic system whereas control rats did not. These data clearly indicate that decreased HPA axis function after 5HT inhibition could be partially compensated by the facilitation of the AVP neuronal activity.

Adrenocorticotropic Hormone↗

PubMed1995

Sex and strain variability in the rat hypothalamo-pituitary-adrenal (HPA) axis function.

In the present investigation, we examined the influence of both genetic background and sex factors in the rat hypothalamo-pituitary-adrenal (HPA) axis function under both basal and post adrenalectomy (ADX) conditions. For these purposes adult female and male rats, from Sprague-Dawley (S-D), Fischer (F344/N), Lewis (LEW/N) and Buffalo (BUF) strains, were decapitated in basal condition or several (2, 7 and 14) days after ADX. Plasma stress hormones levels and adrenal corticosterone (B) concentration as well as peptide (ACTH, CRH and vasopressin, AVP) content in different tissues (anterior pituitary, AP; medial basal hypothalamus, MBH), were then evaluated by specific assays. Our results indicate that: a) despite no sex- and strain-related differences in AP ACTH and MBH ACTH secretagogues in basal condition, there exits a clear sexual dimorphism in plasma ACTH levels as well as in both plasma and adrenal B concentrations, with values significantly higher in females than in males, regardless the strain; b) ADX abolished plasma B levels and increased AP ACTH output in a time-dependent fashion up to the 14th day post surgery; c) AP ACTH content decreased 2 days after ADX, except in BUF female rats, thereafter tending to either recover or increase sham values by two weeks post ADX; d) ADX decreased MBH CRH at all periods studied, except in BUF female animals on day 14; e) ADX clearly diminished MBH AVP only in S-D rats, and f) a sexual dimorphism was also found in AP ACTH in 7-day-ADX S-D rats and in 14-day-ADX S-D and F344/N animals; also, a dimorphic pattern in MBH CRH was found in 7-day-ADX S-D as well as in 14-day-ADX F344/N and LEW/N rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗