leptin and Astrocytoma

Background: Leptin, an adipocytokine functions via the leptin receptor, OB-Rb that contains an intact intracellular\ domain and activates the JAK/STAT signalling cascade. It stimulates growth, migration and invasion of cancer cells in\ vitro potentiating angiogenesis. Recently, the involvement of leptin in tumor progression is being explored. Gliomas\ exhibit poor prognosis, low survival rates demanding for novel therapeutic regimens resulting in discovery of many\ potential biomarkers and pharmaceutical targets. We analysed the potential role of leptin and OB-Rb in carcinogenesis\ of malignant gliomas. Methods: Sixty fresh tissue samples of diffuse gliomas were collected after tumor excision. Real\ time PCR, immunohistochemical (IHC) analysis and western blot analysis were carried out to assess the expression of\ leptin and its receptor. Results: The present study demonstrates the expression of leptin and LepR and their involvement\ in tumor progression. Of the 60 cases, 57 cases (95%) and 53 cases (88.3%) showed amplification for leptin and\ OB-Rb respectively. The expression of these proteins were measured semi-quantitatively and correlated with degree of\ malignancy (p<0.05). The bands were visualised on western blot. Conclusion: Leptin may be valued as a pharmaceutical\ target and anti-leptin compounds could be developed as drugs in mono- or combined therapies for these tumors.

Topics: Adult; Aged; Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Carcinogenesis; Female; Follow-Up Studies; Humans; Leptin; Male; Middle Aged; Neoplasm Grading; Oligodendroglioma; Prospective Studies; Receptors, Leptin

Glioblastoma, the most aggressive type of primary brain tumour, shows worse prognosis linked to diabetes or obesity persistence. These pathologies are chronic inflammatory conditions characterized by altered profiles of inflammatory mediators, including leptin and secreted phospholipase A2-IIA (sPLA2-IIA). Both proteins, in turn, display diverse pro-cancer properties in different cell types, including astrocytes. Herein, to understand the underlying relationship between obesity and brain tumors, we investigated the effect of leptin, alone or in combination with sPLA2-IIA on astrocytoma cell functions. sPLA2-IIA induced up-regulation of leptin receptors in 1321N1 human astrocytoma cells. Leptin, as well as sPLA2-IIA, increased growth and migration in these cells, through activation/phosphorylation of key proteins of survival cascades. Leptin, at concentrations with minimal or no activating effects on astrocytoma cells, enhanced growth and migration promoted by low doses of sPLA2-IIA. sPLA2-IIA alone induced a transient phosphorylation pattern in the Src/ERK/Akt/mTOR/p70S6K/rS6 pathway through EGFR transactivation, and co-addition of leptin resulted in a sustained phosphorylation of these signaling regulators. Mechanistically, EGFR transactivation and tyrosine- and serine/threonine-protein phosphatases revealed a key role in this leptin-sPLA2-IIA cross-talk. This cooperative partnership between both proteins was also found in primary astrocytes. These findings thus indicate that the adipokine leptin, by increasing the susceptibility of cells to inflammatory mediators, could contribute to worsen the prognosis of tumoral and neurodegenerative processes, being a potential mediator of some obesity-related medical complications.

Topics: Animals; Astrocytoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Leptin; MAP Kinase Signaling System; Mice; Phospholipases A2, Secretory; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins pp60(c-src); Receptors, Leptin; Ribosomal Protein S6 Kinases, 70-kDa; TOR Serine-Threonine Kinases; Transcriptional Activation

Diencephalic syndrome is a rare condition associated with central nervous system tumors. The most common presentation is secondary failure to thrive with proper caloric intake and no statural impairment. Despite the importance of this syndrome, little is known of its pathophysiology. Some reports have documented changes in human growth hormone and insulin levels at the onset, whereas others have described endocrine disorders of hypothalamic insufficiency resulting from surgery of the tumor. It has been suggested that the hormonal changes described, such as increased human growth hormone and ghrelin or decreased insulin and leptin levels, are related to a patient's BMI. These findings support the role of these 4 hormones as indicators of the patient's nutritional status but not as mediators or potential therapeutic targets of the disease. We report the case of an infant who initially presented with tumor progression and, after chemotherapy, progressive weight gain and reduced tumor size. Because he presented no hormonal deficiencies or obesity after therapy, we were able to analyze his hormonal status uninfluenced by effects of metabolic treatment or excess weight. Although ghrelin and leptin levels have been related to nutritional status, our patient's leptin levels fell when tumor size decreased and weight increased: an extraordinary finding because leptin concentration is expected to increase with weight gain. This paradoxical response suggests that leptin may be dysregulated in diencephalic syndrome or that the diencephalic astrocytoma may have had an effect on leptin secretion.

Topics: Astrocytoma; Biomarkers; Humans; Hypothalamic Neoplasms; Infant; Leptin; Male; Syndrome

Both proconvulsive and anticonvulsive roles of leptin have been reported, suggesting cell-specific actions of leptin in different models of seizure and epilepsy. The goal of our study was to determine the regulation and function of astrocytic leptin receptors in a mouse model of epilepsy and glutamate-induced cytotoxicity. We show that in pilocarpine-challenged mice developing epilepsy with recurrent seizures after a latent period of 2 weeks, hippocampal leptin receptor (ObR) immunofluorescence was increased at 6 weeks. This was more pronounced in astrocytes than in neurons. In cultured astrocytes, glutamate increased ObRa and ObRb expression, whereas leptin pretreatment attenuated glial cytotoxicity by excess glutamate, reflected by better preserved adenosine triphosphate production. The protective role of astrocytic leptin signaling is further supported by the higher lethality of the astrocyte-specific leptin receptor knockout mice in the initial phase of seizure production. Thus, leptin signaling in astrocytes plays a protective role against seizure, and the effects are at least partially mediated by attenuation of glutamate toxicity. Astrocytic leptin signaling, therefore, may be a novel therapeutic target.

Topics: Animals; Astrocytes; Astrocytoma; Cell Line, Tumor; Convulsants; Epilepsy; Female; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Gliosis; Glutamic Acid; Hippocampus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Neurotoxins; Pilocarpine; Receptors, Leptin; Recurrence; Signal Transduction; Up-Regulation

In this study, we have investigated the role of leptin, soluble leptin receptor(sOb-R), resistin, and insulin secretory dynamics in the development of hypothalamic obesity.. Children who had hypothalamo-pituitary tumor were divided into two groups. First group included obese-overweight (hypothalamic obese = HOB group, n = 23) and second group included non-obese children (hypothalamic non-obese = HNOB group, n = 16). Exogenously obese-overweight children (OB group, n = 22) were included as controls. Basal and second-hour serum glucose and insulin in oral glucose tolerance test (OGTT), basal serum leptin, sOb-R, resistin levels, and homeostasis model assessment (HOMA) indexes were compared between the groups.. Age, sex, and pubertal status were similar in study groups. Median and interquartile ranges of body mass index (BMI) z scores were similar in HOB and OB groups (2.0 (1.5-2.1) and 2.1 (1.8-2.3), respectively). Serum leptin levels corrected for BMI were highest and total leptin/sOb-R ratios (free leptin index (FLI)) tended to be higher in HOB than HNOB and OB groups, indicating leptin resistance (leptin/BMI, 4.0 (1.6-5.2), 1.5 (0.8-3.1), and 2.5 (1.8-3.5); FLI, 2.0 (0.8-3.5), 0.6 (0.3-1.2), and 1.5 (1-2.3) in HOB, HNOB, and OB groups; respectively). Serum resistin levels were similar in groups (2.6 (1.9-3.1), 2.8 (1.7-3.4), and 3.0 (2.2-3.5) ng/ml in HOB, HNOB, and OB groups, respectively). Basal serum glucose, basal and second-hour insulin levels in OGTT, and HOMA index were higher in OB group than the HOB and HNOB groups, indicating insulin resistance in simple obesity; however, increment of insulin to same glycemic load in OGTT was highest in the HOB group indicating insulin dysregulation (p < 0.05).. Hypothalamic obesity seems to be related to both dysregulated afferent (leptin) and efferent (insulin) neural outputs through the autonomic nervous system resulting in energy storage as fat.

Topics: Adolescent; Astrocytoma; Body Mass Index; Child; Craniopharyngioma; Dysgerminoma; Female; Glucose Tolerance Test; Glycemic Index; Homeostasis; Humans; Hypothalamic Neoplasms; Hypothalamus; Insulin; Leptin; Male; Obesity; Receptors, Leptin; Resistin