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Ludwik K Malendowicz

Publications and source records attributed to Ludwik K Malendowicz.

At least 37 records · Page 2Linked to original sources

Effects of beacon on the rat pituitary-adrenocortical axis response to stress.

Beacon is a peptide expressed in the rat hypothalamus and adrenal cortex, which is involved in the central regulation of feeding and inhibits basal and agonist-stimulated glucocorticoid secretion from adrenocortical cells. In vivo studies on beacon have not yet been carried out, and therefore we investigated the effects of a subcutaneous (sc) injection of beacon on the response of rat hypothalamo-pituitary-adrenal axis to stress. Handling and sc injection per se elicited a moderate increase in the plasma concentrations of ACTH and corticosterone, which was counteracted by beacon. Similarly, beacon dampened ACTH and corticosterone responses to ether stress. In contrast, beacon did not affect ACTH response to cold stress, although it was able to induce a moderate lowering in the corticosterone response. Taken together, these findings allow us to draw the following conclusions: i) beacon inhibits handling/injection- and ether stress-activated, but not cold stress-activated, neural mechanism(s) responsible for stimulation of ACTH secretion and the ensuing increase in corticosterone production; and ii) the beacon-induced dampening in corticosterone response to stress also involves a direct inhibitory effect on the adrenal-cortex secretory activity. The physiological relevance of beacon as endogenous anti-stress agent remains to be evaluated.

Adrenocorticotropic Hormone↗

Adrenomedullin and vascular endothelium growth factor genes are overexpressed in the regenerating rat adrenal cortex, and AM and VEGF reciprocally enhance their mRNA expression in cultured rat adrenocortical cells.

Adrenomedullin (AM) is an endogenous regulatory peptide, which exerts growth promoting and neoangiogenic actions in several normal and neoplastic tissues. Evidence has been provided that AM and the pro-angiogenic peptide vascular endothelium growth factor (VEGF) are expressed in the adrenal gland, and we investigated whether their gene transcription is modified in a model of rapid rat adrenal growth, namely regeneration after enucleation and contralateral adrenalectomy. Real-time polymerase chain reaction (PCR) showed that AM and VEGF mRNAs were significantly increased in regenerating adrenals with respect to the intact adrenocortical tissue of sham-operated control rats. Subsequent studies were carried out on dispersed rat adrenocortical cells cultured in vitro for 72 h. Conventional PCR demonstrated that cultured cells expressed AM and VEGF mRNAs. Moreover, real-time PCR showed that 24 h exposure to 10-8 M AM or 50 ng/ml VEGF significantly raised the expression of VEGF and AM, respectively, without affecting that of their own mRNA, suggesting the occurence of autocrine-paracrine up-regulatory mechanisms. Taken together, our findings allow us to conceive that the coordinate up-regulation of AM and VEGF expression may favor cell proliferation and neoangiogenesis, thereby leading to a rapid restoration of morphology and function of regenerating adrenals.

Adrenal Cortex↗

Leptin and leptin receptor expression in the myometrium and uterine myomas: Is leptin involved in tumor development?

Leptin, the product of the obesity (ob) gene, along with its receptors (Ob-Rs), is expressed in several tissues and organs. Evidence has been provided that leptin, in addition to being involved in obesity development, plays a role in the regulation of the female reproductive system, angiogenesis and tumor growth. Uterine myoma is a rather common disease that develops more frequently in obese than lean women, where plasma leptin concentrations are elevated. RT-PCR and Western blotting showed that leptin was expressed, as mRNA and protein, in several uterine myomas but not in normal myometrium, while leptin receptors were expressed in both tissues. Immunocytochemistry indicated that leptin-immunoreactivity was located in both myometrial cells and blood-vessel walls of uterine myomas. Leptin(22-56), at concentrations of 10(-7) and 10(-6) M, enhanced the proliferative activity of both the normal myometrium and myoma cells in primary culture. Taken together, our findings allow us to suggest that leptin, acting through autocrine-paracrine mechanism(s), may be involved in the development of uterine myomas.

Blotting, Western↗

Neuropeptides B and W enhance the growth of human adrenocortical carcinoma-derived NCI-H295 cells by exerting MAPK p42/p44-mediated proliferogenic and antiapoptotic effects.

Neuropeptides B and W (NPB and NPW) are endogenous ligands of two G protein-coupled receptors, named GPR7 and GPR8. GPR7 and GPR8 are expressed in the adrenal cortex, and there is evidence that NPB and NPW stimulate glucocorticoid secretion from human adrenocortical cells by activating protein kinase (PK) A and PKC signaling. To gain insight into the role of NPB and NPW in human adrenal functional regulation, we have investigated their effects on the secretion and growth of the human adrenocortical carcinoma-derived NCI-H295 cell line. NCI-H295 cells were found to express both GPR7 and GPR8 mRNAs, but neither NPB nor NPW (up to 10(-6) M) affected their secretory activity. In contrast, both peptides (from 10(-10) to 10(-6) M) enhanced the growth of NCI-H295 cells, by raising their proliferative activity and lowering their apoptotic deletion rate. NPB and NPW (10(-6) M) stimulated tyrosine kinase (TK) and mitogen-activated PK (MAPK) p42/p44 activities in NCI-H295 cells. Both these effects were blocked by the TK inhibitor tyrphostin-23, while the MAPK p42/p44 inhibitor PD-98059 annulled only MAPK p42/p44 activation. The growth-stimulating effect of 10(-6) M NPB and NPW were not affected by either the PKA and PKC inhibitors H-89 and calphostin-C or the MAPK p38 antagonist SB-293580, but were abolished by both tyrphostin-23 and PD-98059. Taken together, our findings allow us to conclude that GPR7 and GPR8 expressed in NCI-H295 cells: i) are, at variance with those present in normal human adrenocortical cells, uncoupled to PKA- and PKC-dependent cascades, thereby explaining the absence of any secretory response to NPB and NPW; and ii) are coupled to the TK-dependent MAPK p42/p44 signaling, whose activation mediates the proliferogenic and antiapoptotic effect of NPB and NPW.

Adrenocortical Carcinoma↗

Expression of the beacon gene in endocrine glands of the rat.

Beacon gene has been recently identified in the rat hypothalamus, and reported to be overexpressed in obese animals. This pattern of expression suggests that beacon may be involved in the functional regulation of neuroendocrine axes. Hence, we have investigated the expression of beacon in the endocrine system of the rat. Reverse transcription-polymerase chain reaction showed the expression of beacon mRNA in the hypothalamus, adenohypophysis, thyroid gland, adrenal gland, testis, ovary and pancreatic islets. Immunocytochemistry demonstrated the presence of the beacon immunoreactivity in all tissues studied, the staining being very intense in the neurons of paraventricular and supraoptic nuclei, the basophils of adenohypophysis, the parathyroid gland, adrenocortical cells, testis Leydig cells, ovary thecal, granulosa and lutein cells, and pancreatic islets. Due the fact that beacon has been included in the ubiquitin-like protein family, its widespread expression in rat endocrine tissues is not astonishing. The in vivo administration of beacon[47-73] (3.5 nmol/100 body weight) elicited within 60 min a marked decrease in the plasma concentration of ACTH, aldosterone and corticosterone, and a moderate lowering of the blood levels of testosterone and estradiol. This finding suggests that beacon exerts a negative modulatory action on the pituitary-adrenal axis and gonad secretory activity, whose physiological relevance remains, however, to be established.

Animals↗

Ghrelin enhances the growth of cultured human adrenal zona glomerulosa cells by exerting MAPK-mediated proliferogenic and antiapoptotic effects.

Ghrelin is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), two subtypes of which have been identified and named GHS-R1a and GHS-R1b. Evidence has been provided that ghrelin and its receptors are expressed in the adrenal gland, and we have investigated the possible role of the ghrelin system in the functional regulation of the human adrenal cortex. Reverse transcription-polymerase chain reaction detected the expression of both subtypes of GHS-Rs exclusively in the zona glomerulosa (ZG). Ghrelin did not significantly affect either basal or agonist-stimulated aldosterone secretion from cultured ZG cells. In contrast, ghrelin raised proliferative activity and decreased apoptotic deletion rate of ZG cells, the maximal effective concentration being 10(-8) M. The growth effects of 10(-8) M ghrelin on cultured ZG cells were not affected by either the protein kinase (PK)A and PKC antagonists H-89 and calphostin-C or the mitogen-activated PK (MAPK) p38 antagonist SB-293580, but were abolished by both the tyrosine kinase (TK) and MAPK p42/p44 antagonists tyrphostin-23 (10(-5) M) and PD-98059 (10(-4) M), respectively. Ghrelin (10(-8) M) enhanced TK and MAPK p42/p44 activities of ZG cells. Preincubation with 10(-5) M tyrphostin-23 blocked the ghrelin-induced stimulation of both TK and MAPK p42/p44, while preincubation with 10(-4) M PD-98059 only annulled MAPK p42/p44 stimulation. Collectively, our findings allow us to conclude that ghrelin, acting via GHS-Rs exclusively located in the ZG, enhances the growth of human adrenal cortex, through a mechanism involving the activation of the TK-dependent MAPK p42/p44 cascade.

Apoptosis↗

Ghrelin inhibits FGF-2-mediated angiogenesis in vitro and in vivo.

Recent evidence indicates that ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is highly expressed in the cardiovascular system, and in this study we addressed the possibility that ghrelin may affect angiogenesis in vitro and in vivo. Reverse transcription-polymerase chain reaction showed that human umbilical vein endothelial cells (HUVECs) express ghrelin and GHS-R mRNAs. Ghrelin inhibited FGF-2-induced proliferation of HUVECs cultured in vitro, the maximal effective concentration being 10(-8) M, and this effect was annulled by the GHS-R antagonist D-Lys3-growth hormone releasing peptide-6. FGF-2 stimulated HUVEC cultured on Matrigel to form capillary-like structures, and ghrelin (10(-8) M) suppressed this effect. In the chick embryo chorioallantoic membrane in vivo assay, FGF-2 induced a strong angiogenic response, which was counteracted by ghrelin (500 ng). Taken together, these findings suggest that ghrelin acts as an angiostatic molecule and indicate that its activity is comparable to that of a well-known angiostatic agent, i.e., vinblastine. The antiangiogenic activity of ghrelin deserves further investigations, alone or together with other antiangiogenic agents, for the treatment of pathological conditions characterized by enhanced angiogenesis.

Animals↗

Expression of the beacon gene in the rat pancreatic islets: opposite effects of beacon (47-73) protein (ubiquitin-like protein 5) on insulin secretion in vivo and insulin release by isolated islets.

OBJECTIVE: Beacon gene expression is elevated in the hypothalamus of the Israeli sand rat (Psammomys obesus), an animal that is used as a polygenic animal model of obesity and NIDDM. We performed studies aimed at investigating the expression of beacon mRNA and protein in pancreatic islets of the rat and the possible beacon protein effects on insulin secretion. METHODS: Rat pancreatic islets were isolated by the collagenase digestion technique. Beacon mRNA expression was demonstrated in isolated islets using RT-PCR and beacon-like immunoreactivity using immunocytochemistry (ICC) on a sections of Bouin-fixed pancreas. Isolated islets were incubated with 1-100 nmol/L beacon (47-73) protein in normoglycemic medium. Adult female rats were subcutaneously injected with beacon (47-73) at doses 0.35 or 0.7 nmol/100 g body weight and killed after 30 and 60 minutes. RESULTS: RT-PCR results indicate the presence of beacon mRNA in isolated rat pancreatic islets. Beacon-like immunoreactivity is present in all cell types of the Langerhans islet. Beacon inhibits insulin secretion from isolated islets. In contrast, a bolus administration of beacon at a lower dose notably stimulates blood insulin concentration at 30 and 60 minutes of the experiment while the higher dose does not change insulinemia. None of the treatment had an effect on blood glucose concentration. CONCLUSION: This study demonstrated the presence of beacon mRNA in isolated rat islets as well as a direct inhibitory effect of beacon protein on insulin secretion by isolated rat pancreatic islets. The data obtained suggest that beacon may be involved in physiologic regulation of insulin secretion.

Animals↗

Effects of leptin and leptin fragments on steroid secretion and proliferative activity of regenerating rat adrenal cortex.

Leptin, an adipose tissue-secreted hormone, acts via several isoforms of specific receptors (Ob-Rs), which may variously interact with the native leptin molecule and its fragments. Evidence has been provided that leptin affects rat adrenal functions, but the results were rather conflicting depending on the experimental condition examined (e.g. regenerating vs. mature or immature adrenal gland). Hence, we investigated the effects of three subcutaneous injections of murine leptin(1-147) and several leptin fragments (3 nmol/100 g body weight; 28, 16 and 4 h before the sacrifice) on the secretory activity and growth of regenerating rat adrenal cortex. The following leptin fragments were tested: murine leptin(116-130), and human leptin fragments 150-167, 138-167, 93-105, 22-56 and [Tyr]26-39. Leptin(1-147) enhanced plasma concentration of both aldosterone and corticosterone. The blood level of aldosterone was raised by leptin(116-130), leptin(138-167) and leptin(93-105), and that of corticosterone by leptin(93-105) and Tyr-leptin(26-39). Metaphase index (stachmokinetic method with vincristine) was unaffected by leptin(1-147), and lowered by leptin(116-130), leptin(150-167) and leptin(138-167). Collectively, our findings allow us to conclude that leptin and leptin fragments enhance the secretory activity and inhibit the growth of regenerating rat adrenal cortex, the biological activity of leptin being located in the C-terminal segment of its molecule.

Adrenal Cortex↗

Expression of the beacon gene in the rat adrenal gland: direct inhibitory effect of beacon[47-73] on aldosterone secretion from dispersed adrenal zona glomerulosa cells.

Beacon gene was recently identified in the rat hypothalamus, and there is evidence that beacon may be involved in the functional regulation of neuroendocrine axes. Reverse transcription-polymerase chain reaction and immunocytochemistry showed the expression of beacon mRNA and protein in the rat adrenal gland, especially in the cortex. Beacon[47-73], at a concentration over 10(-7) M decreased basal aldosterone secretion from dispersed rat zona glomerulosa (ZG) cells, without affecting the ACTH-stimulated one. Basal and agonist-stimulated corticosterone secretion from dispersed zona fasciculata-reticularis cells and catecholamine release from adrenomedullary slices were unaffected by beacon[47-73]. The suppressive effect of beacon[47-73] on aldosterone secretion from ZG cells was abolished by either H-89 or calphostin-C, which are inhibitors of protein kinase A and C signaling cascades. Taken together, these findings allow us to suggest that beacon can be included in the group of regulatory peptides involved in the fine tuning of ZG secretory activity.

Adrenal Glands↗

Pneumadin in the ventral prostate of rats during postnatal development: a radioimmunological and immunocytochemical study.

We have recently demonstrated that the ventral prostate of adult rats contains high levels of pneumadin (PNM), a decapeptide originally isolated from mammalian lung, and that testosterone is needed for the maintenance of a normal level of the peptide in the prostate. Hence, we have investigated, by radioimmunoassay (RIA) and light ultrastructural immunocytochemistry (ICC), PNM concentration and localization in the rat ventral prostate during postnatal development. RIA showed that PNM content increased steadily from day 20 to day 90 of postnatal life, parallel to the increase in the prostate weight. In contrast, PNM concentration remained rather stable, although it showed a marked rise at day 40 when rat testes are known to reach their full maturation. ICC demonstrated that PNM immunoreactivity was mainly located in the apical pole of epithelial cells of rat ventral prostate, especially in the subcellular organelles involved in protein secretion, i.e. rough endoplasmic reticulum cisternae, vacuoles and granules. Taken together our study suggests the involvement of PNM in the functional control of rat prostate during postnatal maturation, although its exact role remains to be elucidated.

Animals↗

Acute in vivo effects of leptin and leptin fragments on corticosteroid hormone secretion and entero-insular axis in the rat.

Leptin is a 147-amino acid adipose tissue-secreted hormone, which acts via several subtypes of receptors, the main and better known variants of which are named Ob-Ra and Ob-Rb. Structure-activity relationship studies pointed out the importance of the N-terminal and C-terminal amino-acid sequences 22-115 and 116-166, respectively, for the biological and receptor binding activities of leptin. Evidence has been provided that leptin affects corticosteroid-hormone and insulin secretion, and therefore we have investigated in the rat the expression of leptin receptor expression in adrenal cortex and pancreatic islets, as well as the effects of the acute treatment with leptin and leptin fragments 150-167, 138-167, 93-105, 22-56 and 26-39 on the plasma concentrations of aldosterone, corticosterone, insulin and glucagon. Reverse transcription-polymerase chain reaction showed the expression of both Ob-Ra and Ob-Rb mRNAs in adrenal cortex and pancreatic islets, the Ob-Rb expression in pancreas being 2-fold higher than in adrenals. Radioimmuno assay demonstrated that leptin enhanced plasma aldosterone and corticosterone concentrations, decreased plasma insulin concentration, and did not significantly affect glucagon plasma concentration. All leptin fragments tested exerted a corticosteroid-hormone secretagogue action, while only leptin fragments 116-130, 138-167 and 93-105 elicited a sizeable insulin antisecretagogue effect. Taken together these findings suggest that: i) the in vivo acute stimulating effect of leptin on adrenocortical hormone secretion is not connected to specific sequences of its molecule, while the insulinostatic effect is probably mediated by the sequence 93-105; and ii) the secretagogue and antisecretagogue effect of leptin are prevalently mediated by Ob-Ra and Ob-Rb, respectively.

Adrenal Cortex↗

Effects of arginine vasopressin (AVP) on the pituitary-thyroid axis in the rat: Evidence that endogenous AVP, acting via V1 receptors, lowers TSH blood concentration.

We have investigated the effects of the prolonged administration (2 or 8 days) of arginine-vasopressin (AVP), alone or with antagonists of its V1 and V2 receptors (V1-Ra and V2-Ra), on the rat pituitary-thyroid axis. In the 8-day, but not 2-day experiments, AVP raised thyroid weight, and the effect was prevented by V1-Ra. Morphometry showed that the AVP-induced increase in thyroid weight was mainly due to a rise in the stroma volume. In the 2-day, but not 8-day experiments, AVP lowered TSH plasma concentration, and the effect was annulled by V1-Ra. V1-Ra was ineffective per se, while V2-Ra lowered TSH blood level. AVP administration increased the level of circulating thyroid hormones, especially thyroxine (free and total T4). In the 2-day, but not 8-day experiments, this effect of AVP was blocked by both V1-Ra and V2-Ra. When administered alone V1-Ra and V2-Ra induced a small, but significant rise in T4 plasma concentration in both the 2-day and 8-day experiments. Collectively, these findings indicate that: i) AVP administration exerts a transient inhibitory effect on TSH secretion, and a more prolonged stimulatory action on thyroid secretion and growth, both of which are mainly mediated by the V1-R subtype; and ii) endogenous AVP exerts a clearcut tonic inhibitory effect on pituitary TSH release and doubtful regulatory actions on the thyroid gland.

Animals↗

Effect of ghrelin on the apoptotic deletion rate of different types of cells cultured in vitro.

Evidence indicates that ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, controls the growth of several human and rat cell types cultured in vitro. Hence, we have investigated, by using both TUNEL and ELISA assays, the effects of 10(-8) M ghrelin on the basal apoptotic deletion rate of rat osteoblasts and thymocytes, rat and human adrenocortical cells, human umbilical vein endothelial cells, and human aldosteronoma cells cultured in vitro, as well as of the human adrenocortical carcinoma-derived cell lines NCI-H295 and SW-13. Both assays consistently showed that ghrelin did not affect apoptotic rate of normal rat and human cells, but significantly enhanced apoptotic deletion in aldosteronoma, NCI-H295 and SW-13 cell cultures. Due to the central role of apoptosis in the control of tumor growth, these findings, if confirmed in other tumor cell types, could suggest an antitumoral action of ghrelin.

Adrenal Cortex↗

Beacon[47-73] inhibits glucocorticoid secretion and growth of cultured rat and human adrenocortical cells.

Evidence has been recently provided that beacon, an ubiquitin-like protein overexpressed in the hypothalamus of Israeli sand rat, is also expressed in several endocrine glands of the Wistar rat, including adrenal cortex. Moreover, it has been shown that the in vivo administration of beacon[47-73] (hereinafter, beacon) evokes within 60 min a marked decrease in the plasma concentrations of ACTH and corticosterone. Hence, we have investigated the effect of beacon (4x10(-9) or 4x10(-7) M) on the secretion and growth of cultured rat and human zona fasciculata/reticularis (ZF/R) cells. Reverse transcription-polymerase chain reaction detected beacon mRNA in all human adrenal cortexes examined. A 3-h exposure to beacon was ineffective, but prolonged (24 and 96 h) exposures significantly lowered basal corticosterone and cortisol secretion from cultured rat and human ZF/R cells, respectively. Moreover, beacon (4x10(-7) M) counteracted the secretagogue action of 10(-8) M ACTH on cultured cells. The 96-h exposure to beacon concentration-dependently decreased basal proliferation rate of cultured cells, without inducing significant changes in the number of apoptotic and necrotic cells. Beacon (4x10(-7) M) significantly inhibited the proliferogenic effect of 10(-8) M adrenomedullin. In light of the involvement of ubiquitin-like proteins in the control of cell cycle and protein sorting and degradation, the hypothesis is advanced that the inhibitory effect of beacon on the secretion and growth of cultured rat ZF/R cells may be connected to its stimulating effect on proteolysis of steroidogenic enzymes and proteins involved in cell replication.

Adrenal Cortex↗

Effects of neuropeptides B and W on the secretion and growth of rat adrenocortical cells.

Neuropeptide-B (NPB) and neuropeptide-W (NPW) are recently discovered endogenous ligands of the GPR7- and GPR8-receptors (R), which in humans are expressed in the hypothalamus and probably involved in the regulation of energy homeostasis and neuroendocrine axes. GPR8-Rs are absent in rodents, where the GPR8-like-R has been described. Reverse transcription-polymerase chain reaction detected the expression of NPB, NPW, GPR7-R and GPR8-like-R mRNAs in rat adrenocortical cells (both freshly-dispersed and 4-day-cultured cells). NPB did not acutely (60-min exposure) alter basal aldosterone secretion from freshly dispersed zona glomerulosa cells, while NPW raised it. Both NPB and NPW enhanced ACTH-stimulated aldosterone secretion and did not affect either basal or ACTH-stimulated corticosterone production by dispersed zona fasciculata/reticularis (ZF/R) cells. The prolonged (4-day) exposure to NPW, but not NPB, raised corticosterone secretion from cultured ZF/R cells, and both neuropeptides increased the proliferation rate of cultured cells. Taken together, our findings indicate that NPB and NPW affect rat adrenocortical function, so they may be included in that large family of peptides involved in the autocrine-paracrine stimulation of secretion and growth of adrenal cortex.

Adrenal Cortex↗

Ghrelin inhibits in vitro angiogenic activity of rat brain microvascular endothelial cells.

Ghrelin, a 28-amino acid peptide originally isolated from rat stomach, is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R). Evidence has been provided that ghrelin and GHS-Rs are highly expressed in the cardiovascular system, including endothelial cells (ECs), of which they regulate the growth in vitro. It, therefore, seemed worthwhile to investigate the effect of ghrelin on in vitro angiogenesis, using cultures of rat ECs derived from brain microvessels (neuromicrovascular ECs, NECs). ECs, when cultured on a supportive matrix, form a network of tubule-like structures, and such process is enhanced by the classic angiogenic factors, including fibroblast growth factor-2 (FGF-2). After seeding on Matrigel-coated wells, NECs formed within 18 h a meshwork of capillary-like structures; vinblastine (2 x 10(-12) M) disrupted the meshwork, while FGF-2 (50 ng/ml) increased its density. Ghrelin (10(-8) M) exerted a vinblastine-like effect and counteracted the stimulatory action of FGF-2. Computerized image-analysis confirmed these observations. FGF-2 enhanced the proliferation rate and lowered the apoptotic rate of NECs cultured on plastic wells, and ghrelin exerted opposite effects and completely reversed the proliferogenic and antiapoptotic actions of FGF-2. In contrast to vinblastine, ghrelin did not increase lactate dehydrogenase release from cultured NECs, thereby ruling out the possibility that its effects may ensue from an aspecific cytotoxic action. FGF-2 enhanced tyrosine kinase (TK) and mitogen activated protein kinase (MAPK) p42/p44 activities of NECs. Ghrelin significantly decreased TK and MAPK p42/p44 activities and effectively counteracted the effect of FGF-2. Taken together, the present findings indicate that ghrelin exerts a marked in vitro antiangiogenic action, and that the mechanism underlying this effect involves the inhibition of TK/MAPK-dependent cascades.

Animals↗

Effects of leptin and leptin fragments on corticosterone secretion and growth of cultured rat adrenocortical cells.

Compelling evidence indicates that leptin, acting via specific receptors (Ob-Ra and Ob-Rb) modulates adrenocortical-cell secretion. However, the results are controversial, inasmuch as either secretagogue or antisecretagogue effects have been reported. Hence, we decided to study the effects of a 96-h incubation with leptin and leptin fragments 116-130, 150-167, 138-167, 93-105, 22-56 and 26-39 (10(-8) and 10(-6) M) on the secretion and growth of cultured rat adrenocortical cells. Reverse transcription-polymerase chain reaction showed that control cultures expressed both Ob-Ra and Ob-Rb isoforms. As expected, ACTH (10(-8) M) raised corticosterone secretion and lowered proliferation rate of cultured cells. Native leptin elicited ACTH-like effects, while fragment 116-130 was ineffective. Leptin fragments 150-167 and 26-39 stimulated corticosterone production, and fragments 138-167 and 22-56 inhibited it. Fragment 93-105 exerted a dose-dependent biphasic effect on corticosterone secretion (i.e. stimulation and inhibition at the concentration of 10(-8) and 10(-6) M, respectively). Leptin fragment 26-39 enhanced proliferation of cultured cells, while fragments 138-167 and 22-56 were ineffective. Fragments 150-167 and 93-105 displayed proliferogenic and antiproliferogenic effects at the concentration of 10(-8) and 10(-6) M, respectively. Taken together, these findings allows us to conclude that native leptin and its fragments interact differently with Ob-Rs or interact with different Ob-R isoforms, thereby variously modulating secretion and growth of cultured rat adrenocortical cells.

Adrenal Cortex↗