leptin and Adenoma

Equivocal results regarding the role of leptin in colorectal cancer (CRC) and adenoma (CRA) have been reported. A case-control study investigating the association of leptin with CRC risk and clinicopathological characteristics along with meta-analysis of published data on both CRC and CRA were conducted.. Pubmed and Embase were searched for the meta-analysis, comprising 28 case-control studies amounting 3,614 CRC and 1,215 CRA cases, along with 5,220 controls. Meticulous contact with the authors of individual studies was undertaken for the provision of additional data. Pooling of standardized mean differences (SMD), relative risks (RR) and 95 % CI (random effects models), subgroup, sensitivity, and meta-regression analyses were conducted.. The meta-analysis suggested positive association of serum leptin with CRA (RR, 95 % CI 1.35, 1.03 to +1.76), but not CRC either at the pooled analysis on SMDs or RRs (SMD, 95 % CI 0.18, -0.04 to +0.40; RR, 95 % CI 1.04, 0.65 to +1.65). Significant heterogeneity between studies on CRC as well as between studies on CRA providing SMD was noted. Subgroup, meta-regression and sensitivity analyses highlighted potential methodology-, design-, size- and quality-related effect modifiers.. Meta-analysis of current evidence suggests positive association of serum leptin with CRA but not with CRC risk. Given the case-control nature of available studies, the limited number of studies on serum leptin and CRA, and the heterogeneity of CRC studies, carefully designed, prospective studies preferably reporting RRs adjusted for a variety of confounders may be warranted.

Topics: Adenoma; Biomarkers, Tumor; Case-Control Studies; Colorectal Neoplasms; Humans; Leptin; Prognosis; Risk Factors

The normal inverse relationship between leptin and cortisol is lost in chronic hypercortisolism. We studied this apparent dysregulation in patients with Cushing's syndrome to investigate 1) the effect of chronic hypercortisolemia on the circadian rhythm of leptin secretion, 2) the response of leptin after administration of CRH, and 3) the short term effect of curative surgery on leptin. The preoperative morning leptin concentration was 54.2 +/- 8.1 ng/mL, and the nighttime value was 68.6 +/- 9.8 ng/mL, reflecting a mean rise of 32.8 +/- 7.6%, similar to the nocturnal increase observed in normal subjects. By contrast, cortisol's diurnal variation (21.8 +/- 1.7 vs. 16.9 +/- 1.1 mg/dL) was blunted. In women, but not men, body mass index correlated with leptin (P = 0.001). Preoperative ACTH and cortisol (both P < 0.0001), but not leptin levels increased after CRH. Ten days after surgery, basal cortisol values were subnormal (1.1 +/- 0.6 mg/dL), but leptin levels remained unchanged and did not increase after CRH. Body mass index and insulin also remained unchanged. Insulin, but not age, urinary free cortisol, or plasma cortisol correlated with leptin (P < 0.05). In summary, patients with Cushing's syndrome have moderately elevated leptin levels that maintain an intact circadian rhythm but do not respond to acute or subacute alterations of cortisol.

Topics: Adenoma; Adolescent; Adrenocorticotropic Hormone; Adult; Body Mass Index; Child; Circadian Rhythm; Corticotropin-Releasing Hormone; Cushing Syndrome; Female; Follow-Up Studies; Humans; Hydrocortisone; Leptin; Male; Middle Aged; Pituitary Neoplasms; Proteins; Testosterone

Neuroendoscopic surgery of pituitary adenoma has been one of the technologies with rapid progress in neurosurgery in this decade. This method has known advantages and limitations. This study aims to investigate the results of pituitary adenoma treatment using the neuroendoscopy technique in a group of patients. Also, the level of leptin gene expression (LEP), which is produced exclusively in the pituitary gland, was measured for further evaluation. For this purpose, 26 patients who were diagnosed with pituitary adenoma and underwent endoscopic surgery in the hospital between 2018-2022, in terms of age, gender, disease symptoms, functional and non-functional tumor, and neurological examination findings before and after the procedure, complications, and the length of stay in the hospital were investigated. Also, before and 6 months after the operation, blood samples were prepared from patients to evaluate LEP gene expression by real-time PCR technique. The results illustrated that of the 26 patients studied, 14 were men, and 12 were women. Most of the patients were in their third to sixth decades of life. The tumors were non-functioning adenoma in 11 cases, somatotroph adenoma in 9 patients, corticotroph adenoma in 3 cases, and prolactinoma in 3 cases. Seven patients suffered postoperative complications, including 6 cases of reversible complications and one case of patient death. In the 2-year follow-up, 6 cases of tumor recurrence were observed. Also, the evaluation of LEP gene expression showed no significant difference between pre-operative and post-operative expressions. In general, neuroendoscopic surgery in treating pituitary adenoma is a method worthy of attention, considering factors such as fewer complications and a shorter stay in the hospital increase the acceptability of this method.

Topics: Adenoma; Female; Gene Expression; Humans; Leptin; Male; Neoplasm Recurrence, Local; Neuroendoscopy; Pituitary Neoplasms; Retrospective Studies; Treatment Outcome

Obesity is a known risk factor for colorectal cancer (CRC) and adenoma. Obese individuals have higher circulating concentrations of certain endocrine and immune factors produced by adipocytes thought to partially underlie the association between obesity and colorectal neoplasia. Thus, we evaluated the association of plasma concentrations of adiponectin, leptin, and soluble tumor necrosis factor receptor-2 (sTNFR2) with CRC and adenoma.. We ascertained 193 CRC cases and 193 matched controls, and 131 colorectal adenoma cases and 131 matched controls who had had an endoscopy nested in the CLUE II cohort of Washington County, MD. Plasma markers were measured using ELISA. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from conditional logistic regression for quartiles of the plasma markers separately for CRC and adenoma.. Adjusting for leptin and adiponectin, sTNFR2 was positively associated with CRC only in men (Q4 vs. Q1: OR = 3.14, 95% CI 1.11-8.86), which was unchanged adjusting for BMI (3.46, 95% CI 1.19-10.06). Leptin and adiponectin were not associated with CRC risk overall or in men or women. Adiponectin, leptin, and sTNFR2 were not associated with adenoma risk overall or in men or women.. In this study, leptin and adiponectin were not associated with colorectal carcinogenesis and thus do not appear to underlie the association between obesity and colorectal carcinogenesis. sTNFR2, which we measured as a correlate of TNF-α, was positively associated with CRC in men adjusting for BMI, suggesting that TNF-α may influence colorectal carcinogenesis independent of adipocyte production.

Topics: Adenoma; Adipokines; Adiponectin; Aged; Biomarkers; Case-Control Studies; Cohort Studies; Colorectal Neoplasms; Female; Humans; Leptin; Male; Middle Aged; Obesity; Prospective Studies; Risk Factors; Tumor Necrosis Factor-alpha

GH activates agouti-related protein (AgRP) neurons, leading to orexigenic responses in mice. The relationship between serum GH and plasma AgRP, which has been shown to reflect hypothalamic AgRP, has not been evaluated in humans.. To test the hypothesis that central stimulatory actions of GH on hypothalamic AgRP could be reflected in plasma AgRP in acromegaly.. We studied 23 patients with active acromegaly before and for ≤2 years after surgical (n = 13) or GH receptor antagonist therapy with pegvisomant (n = 10), and 100 healthy subjects with morning fasting blood samples for AgRP, leptin, GH, and IGF-1 and anthropometric measurements.. The plasma AgRP levels were higher in those with active acromegaly than in the matched healthy subjects [median, 100 pg/mL; interquartile range (IQR), 78 to 139 pg/mL vs median, 63 pg/mL; IQR, 58 to 67 pg/mL; P < 0.0001]. Plasma AgRP decreased from before to after surgery (median, 102 pg/mL; IQR, 82 to 124 pg/mL vs median, 63 pg/mL; IQR, 55.6 to 83 pg/mL; P = 0.0024) and from before to during pegvisomant therapy (median, 97 pg/mL; IQR, 77 to 175 pg/mL vs median, 63; IQR, 61 to 109 pg/mL; P = 0.006). The plasma AgRP level correlated with GH (r = 0.319; P = 0.011) and IGF-1 (r = 0.292; P = 0.002). In repeated measure analysis, AgRP was significantly associated with IGF-1.. Our data have provided evidence of a stimulatory effect of GH on plasma AgRP in humans. The levels were greater in active acromegaly and decreased in parallel with GH and IGF-1 decreases with acromegaly treatment. Data from mice suggest that AgRP may mediate some of the known effects of GH on energy metabolism. This warrants further study in patients with acromegaly and other populations.

Topics: Acromegaly; Adenoma; Adult; Agouti-Related Protein; Female; Hormone Antagonists; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Neurosurgical Procedures; Pituitary Neoplasms; Receptors, Somatotropin; Treatment Outcome; Young Adult

Leptin phenotype has been suggested to be a possible biomarker for the diagnosis and prognosis of different neoplasms. Nonetheless, there are conflicts among the outcomes found in several tumors, and little is proven concerning the correlation between the phenotype of leptin and its clinical significance in colorectal carcinomas. This study will describe the phenotype of leptin in colorectal adenocarcinomas, and investigate its correlation with clinicopathological factors.Two hundred and twenty eight tissue samples include 155 colorectal carcinomas, 40 adenomas, and 33 noncancerous cases were utilized in constructing tissue microarrays which have been used in the revealing of leptin expression using leptin monoclonal antibody and immunohistochemistry staining protocol.Immunoexpression of leptin was recognized in 145 (93.5%) of colorectal tumors and 56 (76.7%) cases of control group. Histotype was considerably associated with leptin phenotype (P = .000), there is up regulation in leptin expression in colorectal carcinoma cases. Significantly higher proportion of negative leptin immunostaining cases were observed in tumors which have size more than 5 cm (P = .045). Whereas, significant different survival patterns were observed in positive cases regarding tumor size, lymphovascular invasion, distant metastasis, local recurrence and relapse of disease (P-values .046, .011, .000, .013, and .001, respectively). On the other hand, positive leptin staining colorectal tumors with size <5 cm, and with no distant metastases, local recurrence, or disease relapse had significantly better survival estimates. However, leptin immunostaining did not show noteworthy associations with age, gender, differentiation, tumor location, stage, margins involvement, lymphovascular invasion, and lymph node metastasis.The current study shows up regulation in leptin expression in colorectal adenocarcinoma compared with noncancerous control cases. Thus, immunohistochemical staining of leptin in colorectal cancer could be a helpful tool in the prediction of prognosis and survival pattern of colorectal cancer with certain clinicopathological factors (tumor size, lymphovascular invasion, distant metastasis, local recurrence, and relapse of disease).

Topics: Adenocarcinoma; Adenoma; Adult; Biomarkers, Tumor; Case-Control Studies; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Leptin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Recurrence, Local; Phenotype; Prognosis; Saudi Arabia; Survival Analysis; Tumor Burden

We asked if leptin and its cognate receptor were present in normal and diseased parathyroid glands, and if so, whether they had any functional effects on parathyroid hormone (PTH) secretion in parathyroid neoplasms.. The parathyroid glands acting through PTH play a critical role in the regulation of serum calcium. Based on leptin's recently discovered role in bone metabolism, we hypothesized these glands were the sites of a functional interaction between these 2 hormones.. From July 2010 to July 2011, 96 patients were enrolled in a prospective study of leptin and hyperparathyroidism, all of whom were enrolled based on their diagnosis of hyperparathyroidism, and their candidacy for surgical intervention provided informed consent. Immediately after parathyroidectomy, 100 to 300 mg of adenomatous or hyperplastic diseased parathyroid tissue was prepared and processed according to requirements of the following: in situ hybridization, immunohistochemistry, immunofluorescence by conventional and spinning disc confocal microscopy, electron microscopy, parathyroid culture, whole organ explant, and animal model assays.. Leptin, leptin receptor (long isoform), and PTH mRNA transcripts and protein were detected in an overlapping fashion in parathyroid chief cells in adenoma and hyperplastic glands, and also in normal parathyroid by in situ hybridization, qRT-PCR, and immunohistochemistry. Confocal microscopy confirmed active exogenous leptin uptake in cultured parathyroid cells. PTH secretion in explants increased in response to leptin and decreased with leptin receptor signaling inhibition by AG490, a JAK2/STAT3 inhibitor. Ob/ob mice injected with mouse leptin exhibited increased PTH levels from baseline.. Taken together, these data suggest that leptin is a functionally active product of the parathyroid glands and stimulates PTH release.

Topics: Adenoma; Animals; Cells, Cultured; Humans; Hyperparathyroidism; Hyperplasia; Immunohistochemistry; Leptin; Mice, Knockout; Microscopy, Confocal; Microscopy, Fluorescence; Microscopy, Immunoelectron; Parathyroid Glands; Parathyroid Hormone; Parathyroid Neoplasms; Prospective Studies; Receptors, Leptin; RNA, Messenger

There is an established link between obesity related metabolic derangement and colorectal cancer development. Recently, we developed a metabolic-colorectal cancer risk score. In this follow-up study, we studied its association with colorectal neoplasm by measuring two major metabolic syndrome biomarkers, leptin and adiponectin.. To evaluate the serum levels of leptin and adiponectin in patients with colorectal polyps and colorectal cancer and to determine any correlation with metabolic risk score.. In total, 130 individuals were studied: 30 controls without colonic pathology, 18 with colonic adenoma (CAP), and 82 with colorectal adenocarcinoma (CRC, 17 cases of T1-2 and 65 cases of T3-4). The metabolic risk scores in CAP and T1-2 CRC were higher than those in the controls and T3-4 CRC cases. There were no statistically significant differences in leptin levels among CAPs, CRCs, and controls. Both leptin and adiponectin levels reflected differences in body mass index and metabolic risk scores. Cases in the CAP group and early T-stage CRC groups had lower adiponectin levels (14.03 and 13.01 mg/ml, respectively) than the no polyps group (19.5mg/ml, p = 0.03). The average serum adiponectin level in the invasive cancer group (18.5 ng/ml) was comparable with that of the control group.. The level of serum adiponectin was positively correlated with the metabolic risk score. Decreased serum adiponectin was significantly associated with the development of colorectal adenoma and early stage colorectal carcinoma.

Topics: Adenocarcinoma; Adenoma; Adiponectin; Biomarkers, Tumor; Case-Control Studies; Cell Transformation, Neoplastic; Colonic Polyps; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Leptin; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Risk Factors

Interplay between adipose tissue and adrenal glands has been recently suggested, without well-founded actions of locally adipose tissue surrounding the adrenal glands.. We hypothesized that the local expression of leptin and adiponectin can be associated with pathological changes of the adrenal glands.. We evaluated RT-PCR of leptin and adiponectin mRNA expression from the adipose tissue surrounding adrenal glands in 30 patients, collecting adipose tissue surrounding the adrenal neoplasms, peri-renal and subcutaneous depots.. Leptin mRNA levels from adrenal neoplasia and peri-renal fat were significantly higher in aldosterone-producing adenoma than in nonfunctioning adenomas (P < 0.001 and P < 0.02, respectively). In patients with Cushing's syndrome leptin mRNA levels were significantly higher in adrenal fat than in peri-renal (P < 0.05) and subcutaneous adipose tissue (P < 0.001). Adiponectin mRNA expression from adrenal neoplasia was significantly lower than that from peri-renal and subcutaneous fat depots (P < 0.05). Leptin and adiponectin plasma levels significantly correlated with their mRNA expression from the fat depot surrounding the adrenal neoplasia.. Our findings suggest an active role of the fat depot surrounding the adrenal neoplasia, with local secretion of leptin and adiponectin.

Topics: Adenoma; Adiponectin; Adipose Tissue; Adrenal Gland Neoplasms; Adult; Aged; Female; Humans; Leptin; Male; Middle Aged; RNA, Messenger

Patients with craniopharyngioma (CP) have disturbances of the hypothalamic-pituitary axis and serious comorbidities such as obesity. We hypothesized that the secretion of hormones regulating the nutritional status is altered in adult patients with CP compared with patients with non-functioning pituitary adenoma (NFPA).. WE INCLUDED 40 CP (50% MALES, MEAN AGE: 49.6±14.3 years) and 40 NFPA (72.5% males, mean age: 63.4±9.8 years) patients. We measured glucose, insulin, leptin, total ghrelin, peptide-YY (PYY) and cholecystokinin (CCK) during oral glucose tolerance test (OGTT). Fat mass (FM) was determined by dual X-ray absorptiometry.. Gender distribution was not significantly different, but CP patients were significantly younger (P<0.001). CP patients had significantly higher BMI and FM than NFPA patients (BMI 32±8 vs 28±4 kg/m(2), P=0.009 and FM 37±9 vs 33±9%, P=0.02). Fasting glucose level (84±12 vs 78±11 mg/dl, P=0.03), leptin (27.9±34.2 vs 11.9±11.6 μg/l, P=0.008) and leptin levels corrected for percentage FM (0.66±0.67 vs 0.32±0.25 μg/l%, P=0.005) were significantly higher in CP than in NFPA patients, whereas ghrelin was significantly lower (131±129 vs 191±119 ng/l, P=0.035). Insulin, PYY and CCK did not differ significantly between groups. After glucose load, leptin decreased significantly in CP patients (P=0.019). In both groups, ghrelin decreased significantly during OGTT (both P<0.001). The percentage decline was significantly smaller for CP. PYY and CCK increased equally after glucose in both groups.. Our patients with CP have more metabolic complications than our patients with NFPA. The levels of leptin and ghrelin at fasting status and after glucose seem to be altered in CP, whereas changes in insulin, PYY and CCK do not seem to be responsible for the metabolic changes in these patients.

Topics: Absorptiometry, Photon; Adenoma; Adult; Aged; Appetite Regulation; Blood Glucose; Body Fat Distribution; Case-Control Studies; Cholecystokinin; Craniopharyngioma; Female; Ghrelin; Glucose Tolerance Test; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Peptide YY; Pituitary Neoplasms

Obesity is associated with certain types of cancer, including gastric cancer. However, it is still unclear whether obesity-related cytokine, leptin, is implicated in gastric cancer. Therefore, we aimed to investigate the role of leptin in gastric cancer. The expression of leptin and its receptor, Ob-R, was assessed by immunohistochemical staining and was compared in patients with gastric adenoma (n=38), early gastric cancer (EGC) (n=38), and advanced gastric cancer (AGC) (n=38), as a function of their clinicopathological characteristics. Gastric cancer cell lines were studied to investigate the effects of leptin on the signal transducer and activator of transcription-3 (STAT3) and extracellular receptor kinase 1/2 (ERK1/2) signaling pathways using MTT assays, immunoblotting, and inhibition studies. Leptin was expressed in gastric adenomas (42.1%), EGCs (47.4%), and AGCs (43.4%). Ob-R expression tended to increase from gastric adenoma (2%), through EGC (8%), to AGC (18%). Leptin induced the proliferation of gastric cancer cells by activating STAT3 and ERK1/2 and up-regulating the expression of vascular endothelial growth factor (VEGF). Blocking Ob-R with pharmacological inhibitors and by RNAi decreased both the leptin-induced activation of STAT3 and ERK1/2 and the leptin-induced expression of VEGF. Leptin plays a role in gastric cancer by stimulating the proliferation of gastric cancer cells via activating the STAT3 and ERK1/2 pathways.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Cell Line, Tumor; Cell Proliferation; Female; Gastric Mucosa; Humans; Immunohistochemistry; Leptin; Male; MAP Kinase Signaling System; Middle Aged; Obesity; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Stomach; Stomach Neoplasms; Vascular Endothelial Growth Factor A

Obesity increases the risk of colorectal cancer and adenomatous polyp, and one of the underlying mechanisms of this increase is considered to be due to the growth promoting effects of adipokines, such as leptin. In order to investigate this finding, leptin expression in the colonic tissue and blood leptin concentration of the colonic adenoma patients were compared to those of the control group.. Colonic adenoma tissues were obtained by polypectomy (n=60). In these patients, normal colonic mucosa at remote areas from the polyp was also obtained and blood samples were collected as well. Age and sex matched control subjects were selected among those who showed normal colonic mucosa in health screening colonoscopy (n=60).. There was no significant difference in serum leptin concentration between the colonic adenoma patients and control subjects. Leptin expression was noted in 43.3% of the colonic adenomas, but only in 6.7% of normal colonic mucosa from the control subjects (p<0.01). There were ten cases of concurrent adenocarcinoma in situ in adenoma patients, eight cases of which expressed leptin (p=0.01). In adenoma group, leptin expression rate was significantly high in larger adenomas and in obese patients (p<0.05). However, there was no statistically significant relationship between leptin expression in colonic mucosa and serum leptin level.. Leptin expression was more frequently observed in colonic adenomas, especially in larger adenomas associated with adenocarcinoma in situ, but blood leptin level was not related to tissue leptin expression. Leptin expression was more frequently observed in obese patients from the adenoma group. Therefore, leptin may play an important role in colonic tumorigenesis and progression, especially in obese patient.

Topics: Adenoma; Adult; Aged; Body Mass Index; Colonic Neoplasms; Colonic Polyps; Female; Humans; Intestinal Mucosa; Leptin; Male; Middle Aged; Obesity; Odds Ratio; Waist Circumference

It has been shown that acromegaly is characterized by an autonomic imbalance and by marked sympathoinhibition. However, there is no information available as to whether adrenergic inhibition is confined to selected vascular districts or, rather, is generalized. We examined 17 newly diagnosed active acromegalic patients without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy and 14 healthy subjects matched for age, sex and body mass index. For each subject, we collected information regarding anthropometric parameters and echocardiography, and collected plasma samples to investigate anterior pituitary function, glucose and lipid metabolism and plasma leptin levels. Beat-to-beat mean arterial pressure, heart rate and efferent post-ganglionic muscle and skin sympathetic nerve traffic (MSNA and SSNA, respectively; determined by microneurography) were measured. Both MSNA and SSNA were recorded in a randomized sequence over two 30 min periods. Measurements also included evaluation of SSNA responses to emotional stimulus. In addition to significant reductions in plasma leptin levels, acromegalic patients had markedly decreased MSNA compared with the healthy controls. There were no significant differences in SSNA between the two groups, either under basal conditions or in responses to arousal stimuli. There was a significant and direct correlation between MSNA and plasma leptin levels, but not between plasma leptin and SSNA. These data provide the first evidence that the sympathetic inhibition characterizing the early phase of acromegaly is not generalized to the entire cardiovascular system.

Topics: Acromegaly; Adenoma; Adrenergic Neurons; Adult; Autonomic Nervous System; Cardiovascular System; Female; Growth Hormone-Secreting Pituitary Adenoma; Humans; Leptin; Male; Middle Aged; Muscle, Skeletal; Neural Inhibition; Peripheral Nervous System; Pituitary Gland, Anterior; Severity of Illness Index; Skin; Sympathetic Nervous System; Synaptic Transmission

To investigate the expressions of leptin and peroxisome proliferator-activated receptor γ (PPARG) in relation to body mass index (BMI).. We evaluated leptin and PPARG expression in 30 adenomas over 1 cm in size by immunohistochemical staining. In addition, clinicopathologic features including BMI were assessed.. PPARG and leptin expression showed a strong positive correlation (P = 0.035). The average BMI of the leptin-positive group was higher than that of the leptin-negative group (25.4 ± 3.4 kg/m(2)vs 22.6 ± 2.4 kg/m(2), P = 0.018), and leptin expression was significantly correlated with high BMI (P = 0.024). Leptin expression was more frequently observed in intermediate/high grade dysplasia than in low grade dysplasia (P = 0.030). However, PPARG expression was not correlated with BMI and grade of dysplasia.. BMI has influenced on the leptin expression of colorectal adenoma. The exact mechanism underlies the strong correlation between leptin and PPARG expression needs further study.

Topics: Adenoma; Adult; Body Mass Index; Cell Line, Tumor; Colorectal Neoplasms; Female; Humans; Leptin; Male; Microarray Analysis; Middle Aged; Obesity; PPAR gamma

The possible role of leptin in colorectal tumors has been investigated in previous studies; however, to date, the conclusions remain under debate. Therefore, we investigated the serum leptin levels in colorectal adenoma patients. In addition, expression of the leptin receptor, and the leptin receptor-mediated signaling pathways were investigated in biopsy specimens collected from human patients with colorectal adenoma. No significant difference in the mean serum leptin level was observed between the colorectal adenoma patients and the control subjects; however, increased expression and activation of the leptin receptor, as indicated by findings such as the phosphorylation of Tyr 1141, was observed in the colorectal adenoma tissues. In addition, activation of the JAK/STAT signaling pathway mediated by the leptin receptor and increased transcriptional regulation of downstream target molecules were observed in colorectal adenomas compared with the non-adenoma tissues. These results indicate STAT3-mediated leptin receptor signaling pathways may be activated in human colorectal adenomas.

Topics: Adenoma; Blotting, Western; Colorectal Neoplasms; Enzyme Activation; Female; Humans; Immunohistochemistry; Leptin; Male; Middle Aged; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor

Although a number of recent studies have reported the involvement of leptin in colorectal carcinogenesis, findings are contradictory and difficult to interpret. Our group has previously reported that leptin signaling might have an important role in the development of colorectal adenomas. In this study, we investigated leptin signaling in colorectal carcino-genesis focusing in particular on the differences in leptin signaling between colorectal adenoma and cancer. Whereas no significant differences in the serum leptin levels were observed among normal control subjects and adenoma/cancer patients, increased expression and activation of the long form leptin receptor (ObRL) was observed in colorectal adenoma and cancer tissues compared with the normal colorectal tissues. However, no significant differences were observed between the colorectal adenoma and cancer tissues. Significant increases in the phosphorylation levels of important molecules of the JAK/STAT signaling pathway, located downstream of leptin signaling, and transcriptional regulation of STAT3-downstream target molecules were observed in colorectal adenoma tissue compared with the findings in normal colorectal tissues. Furthermore, these changes were significantly more pronounced in colorectal cancer compared to colorectal adenoma tissues. This is the first analysis of leptin and JAK/STAT signaling in a human colorectal adenoma-carcinoma sequence. These results suggest that the STAT3-mediated leptin signaling through the activation of ObRL may be involved in colorectal carcinogenesis, both in adenoma formation and in the progression to cancer. STAT3 signaling in colorectal cancer may be mediated not only by leptin but by other factors.

Topics: Adenoma; Case-Control Studies; Colorectal Neoplasms; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Janus Kinases; Leptin; Male; Middle Aged; Phosphorylation; Receptors, Leptin; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor

Primary aldosteronism (PA) has been recently associated with an unfavorable cardiometabolic profile. However, whether pro- and antiinflammatory adipokines levels can vary in PA is unknown.. We evaluated the circulating levels of resistin, leptin, and adiponectin, echocardiographic left ventricle (LV) parameters, and the prevalence of metabolic syndrome (SM) in subjects with PA.. Seventy-five subjects with established diagnosis of PA and 232 consecutive individuals with known or suspected hypertension were enrolled.. Plasma adipokine levels and echocardiographic parameters were calculated. Prevalence of SM was also estimated.. Among the 75 PA subjects, 37 patients were affected by aldosterone-producing adenoma and 38 by idiopathic hyperaldosteronism; 40 subjects were affected by essential hypertension (EH) and SM (EH SM+); 152 subjects were affected by EH without SM (EH SM-); and 40 subjects were normotensive (NT). Subjects with PA had the highest plasma resistin levels among the four groups (P < 0.01). Plasma resistin concentration was significantly higher in PA subjects when compared with EH SM+ individuals (P < 0.01) and EH SM- subjects (P < 0.01). PA subjects showed the higher LV mass and left atrium than EH individuals, irrespectively of the presence of SM (P < 0.01 for both). Plasma resistin levels was significantly correlated with ejection fraction and LV end-diastolic volume. The prevalence of SM was higher in PA subjects than in those with EH (25.4 vs. 20.3%).. Our data suggest that elevated aldosterone levels is associated with elevated circulating resistin levels and cardiac morphological changes independently of the presence of SM.

Topics: Adenoma; Adiponectin; Adult; Aged; Aldosterone; Biomarkers; Blood Glucose; Blood Pressure; C-Reactive Protein; Cholesterol; Echocardiography; Female; Heart Ventricles; Humans; Hyperaldosteronism; Hypertension; Leptin; Male; Metabolic Syndrome; Middle Aged; Resistin; Young Adult

Obesity is a risk factor for colorectal cancer and adenomatous polyps. The increased prevalence of neoplasia coupled with the observation that obesity may be associated with a suboptimal bowel preparation may diminish the adequate detection of adenomas for obese who undergo colonoscopy. The colonic complications of obesity are reviewed in this article.

Topics: Adenoma; Animals; Body Mass Index; Colonic Diseases; Colonoscopy; Colorectal Neoplasms; Comorbidity; Diverticulitis, Colonic; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; Metabolic Syndrome; Obesity

Adipocytokines are adipocyte-secreted hormones associated with some malignancies such as colorectal, breast, and prostate cancer. We hypothesized that changes in the levels of adipocytokines may indicate the carcinogenesis and progression of colorectal cancer and adenoma, and investigated the association of the blood levels of several adipocytokines through a case-control study. Blood levels of adiponectin, leptin, resistin, visfatin, and C-peptide at diagnosis were measured in 115 colorectal cancer patients and 115 age-, sex-, and body mass index-matched controls. The same analysis was performed in 72 colorectal adenoma patients and 72 controls. Logistic regression models were used for estimating odds ratios and 95% confidence intervals, and one-way anova was performed to determine the prevalence of each variable between two or more groups. Resistin and visfatin levels in cancer patients were significantly higher than those of controls on multivariate analysis (P = 0.03 and P < 0.01, respectively). Stage progression significantly correlated with resistin and visfatin levels (P < 0.01 for both). The adiponectin level in adenoma patients was significantly lower than that of controls on multivariate analysis (P = 0.04). Its level was inversely correlated with the number of adenoma (P = 0.02), but not correlated with the size of adenoma. Resistin and visfatin may be good biomarkers of colorectal malignant potential and stage progression. Adiponectin level may be a good biomarker of colorectal adenoma.

Topics: Adenoma; Adipokines; Adiponectin; Adult; Aged; Biomarkers, Tumor; Body Mass Index; C-Peptide; Colorectal Neoplasms; Cytokines; Female; Humans; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Resistin

Serum adiponectin, leptin, C-peptide, and homocysteine are indicators for obesity, hyperinsulinemia, and chronic inflammation, which have all been associated with colorectal cancer.. To determine whether serum adiponectin, leptin, C-peptide, and homocysteine are associated with fat, fiber, fruit and vegetable, flavonol, or dry bean intake and colorectal adenoma recurrence.. Using logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (95% CI) for adenoma recurrence in 627 participants from the control arm of the Polyp Prevention Trial, a 4-year trial that examined the effectiveness of a low-fat, high-fiber, high-fruit and vegetable diet on adenoma recurrence.. Serum concentrations of C-peptide and homocysteine were inversely related to fiber, fruit and vegetable, and flavonol intake and positively related to percentage of calories from fat (all P(trend) < or = 0.01). High homocysteine concentrations were associated with any (4th versus 1st quartile: OR, 2.26; 95% CI, 1.30-3.94) and more than one adenoma recurrence (OR, 2.11; 95% CI, 1.01-4.40). Individuals in the highest, versus lowest, tertile of serum leptin concentration had a decreased risk of advanced adenoma recurrence (OR, 0.22; 95% CI, 0.06-0.79).. Our results suggest that serum homocysteine may serve as an indicator of dietary exposure, including a low-fat and high-fiber, high-fruit and vegetable, and high-flavonol diet, as well as colorectal adenoma recurrence.. Discovering biomarkers that are both modifiable and can predict cancer risk is critical. We identified serum homocysteine as a novel indicator that is modified by diet and predicts risk of adenoma recurrence.

Topics: Adenoma; Adiponectin; Adult; Aged; Aged, 80 and over; C-Peptide; Colorectal Neoplasms; Diet; Female; Follow-Up Studies; Homocysteine; Humans; Leptin; Male; Middle Aged; Neoplasm Recurrence, Local; Recurrence; Risk Factors

Obesity has been associated with an increased risk of colorectal neoplasia, but the mechanisms of this potential association have not been elucidated. We hypothesized that the adipokines adiponectin, leptin, and tumor necrosis factor-alpha (TNF-alpha) may mediate an association between obesity and colorectal cancer. We measured plasma concentrations of total and high-molecular-weight (HMW) adiponectin, leptin, and TNF-alpha in healthy volunteer examinees who underwent total colonoscopy between February 2004 and February 2005, and conducted a case-control study consisting of 778 cases and 735 controls. An inverse association of total and HMW adiponectin was observed with colorectal adenoma (P trend < 0.001 and 0.03, respectively). Further, total adiponectin interacted with leptin, but not TNF-alpha, in relation to colorectal adenoma (P interaction = 0.007). An inverse association of total adiponectin with colorectal adenoma was apparent in the highest two tertiles of leptin, particularly the middle (P trend < 0.001), whereas a positive association of leptin was obvious in the lowest tertile of total adiponectin (P trend = 0.01) after adjusting for potential confounders and body mass index, which is a major determinant of insulin resistance. Adiponectin may exert an anticarcinogenic effect on the large intestine by interfering with leptin, whereas leptin could conversely exert a carcinogenic effect under conditions of a lower abundance of adiponectin. Our findings provide the first epidemiologic evidence for interactive effects of adiponectin and leptin in the early stage of colorectal tumorigenesis, distinct from their involvement in insulin resistance.

Topics: Adenoma; Adiponectin; Adult; Aged; Case-Control Studies; Colorectal Neoplasms; Female; Humans; Leptin; Male; Middle Aged; Risk Factors; Tumor Necrosis Factor-alpha

Colorectal adenoma and cancer are known to be associated with obesity. Leptin, an adipocyte-derived hormone that plays a crucial role in obesity has been suggested as a growth factor in colon cancer. However, the association between adenoma and leptin remains controversial. We evaluated the leptin expression in human colorectal adenoma and its correlation to clinicopathologic factors.. Leptin expression was assessed by immunohistochemistry in 91 samples of colorectal adenoma larger than 5 mm, which were removed by endoscopic polypectomy. All patients underwent colonoscopy for cancer screening at Seoul Paik Hospital from 2007 to 2008 and we only included the patients less than 50 years of age. Leptin expression and its relationship with clinicopathologic features were analyzed.. Eighty samples were available for the interpretation of leptin expression and showed positive in 42 (52.5%) cases and negative in 38 (47.5%) cases. As body mass index (BMI) increased based on World Health Organization (WHO) classification the positivity of leptin expression also increased (ptrend=0.02). In leptin positive group, the correlation of leptin expression with adenoma size and histological showed positive tendency without statistical significance.. Leptin expression of colorectal adenoma was associated with BMI. The question of whether leptin contributes to colorectal adenoma development is unresolved and will require additional studies.

Topics: Adenoma; Adult; Body Mass Index; Colonoscopy; Colorectal Neoplasms; Female; Humans; Leptin; Male; Middle Aged; Obesity

Leptin, adiponectin, and resistin are the proteins secreted by adipocytes, which affects the metabolism. While the role of leptin in colon carcinogenesis is documented, the effect of adiponectin and resistin remains unclear. It has been indicated that while leptin may potentiate the cancer cells growth, adiponectin and resistin may act oppositely.. The aim of this study is to determine the concentration of leptin, adiponectin, and resistin in patients with adenomatous polyps and colorectal cancer.. The serum concentration investigated adipohormones had been measured with ELISA in 37 patients with colorectal adenomas, 36 with colorectal cancer (CC) and in 25 controls with no colorectal pathology. Endoscopically removed polyps and CC biopsies had been evaluated with histopathology. Mean BMI value was calculated for all patients.. Among 37 adenomas, 25 revealed high-grade dysplasia (HGD) and 12 low-grade dysplasia (LGD). All cases of CC were adenocarcinomas. No difference in the level of investigated adipohormones in serum between patients with HGD and LGD polyps was observed. The serum concentration of leptin and adiponectin in CC patients was lower than in patients with adenomas (p < 0.05; p < 0.05, respectively) as well as in controls (p < 0.01; p < 0.05, respectively). The concentration of resistin in CC was not significantly different in the adenoma group (p > 0.05) but higher than in controls (p < 0.05). There was a correlation between adiponectin and leptin serum concentration (r = 0.61).. We conclude that serum concentration of adiponectin and resistin may play an important role in colon carcinogenesis. We also assume that leptin may possibly have the prognostic value useful in clinical practice and its concentration is independent of BMI value.

Topics: Adenoma; Adiponectin; Case-Control Studies; Colonoscopy; Colorectal Neoplasms; Female; Humans; Leptin; Male; Middle Aged; Neoplasm Staging; Resistin

Leptin, the product of the ob gene, is an adipocyte-derived neurohormone that regulates body fat storage and feeding behavior. Some studies have suggested that leptin has growth-factor-like functions in epithelial cells and its abnormal expression may be involved in cancer development and progression. We investigated leptin expression in normal and neoplastic colorectal tissues and its association with clinicopathological features and clinical outcome in colorectal adenocarcinoma patients. Leptin expression was evaluated on the tissue microarray of 44 normal colon mucosal tissues, 44 adenomatous polyps, and 437 colorectal adenocarcinomas by immunohistochemistry. Data were analyzed by chi-square test, one-way analysis of variance (ANOVA), Cox regression hazards model, and log-rank test with Kaplan-Meier curves. Frequency of leptin expression was dramatically increased from normal colonic mucosa (2/44, 4.5%) to adenomas (13/44, 29.5%) and adenocarcinomas (321/437, 73.5%) as neoplastic progression. Interestingly, leptin expression was correlated with favorable tumor features in depth of invasion (p = 0.033), lymph node metastasis (p = 0.019), American Joint Committee on Cancer (AJCC) and Dukes' stage (p = 0.021 and p = 0.005, respectively), differentiation (p = 0.010), and lymphatic invasion (p = 0.003). In univariate survival analysis, patients with leptin-positive adenocarcinoma revealed better overall and disease-free survivals (p = 0.032 and p = 0.004, respectively, log-rank test). In multivariate survival analysis with Cox proportional hazards model, leptin expression was an independent prognostic marker of disease-free survival (p = 0.009). We conclude that leptin was gradually expressed during the normal-adenoma-adenocarcinoma sequence, suggesting an association in colorectal carcinogenesis. In addition, high leptin expression was an indicator of favorable tumor features and better survival of colorectal cancer patients.

Topics: Adenocarcinoma; Adenoma; Adenomatous Polyps; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Child; Colon; Colorectal Neoplasms; Female; Humans; Immunoenzyme Techniques; Leptin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Phenotype; Survival Rate; Tissue Array Analysis; Young Adult

We investigated the role of leptin receptor (Ob-R) and its relationship with phosphatidylinositol 3-kinase (PI3K)/AKT activation in colorectal carcinomas (CRCs) tissues followed by in vitro studies using a panel of CRC cell lines. Obesity serves an important risk factor of several cancers including CRC that ranks as the second most common cancer in Saudi Arabia. High levels of adipokine leptin (Ob) and its Ob-R are seen in obesity and also in various carcinomas including CRC. We investigated the proliferative and antiapoptotic effect of Ob on human CRC cell lines Caco-2, HT-29 and SW-840 and the role of PI3K/AKT-signaling pathway in mediating these actions. Then the expression of Ob-R and its relationship with clinicopathological features was analyzed in 448 CRC, 229 normal colon mucosa and 24 colorectal adenomas using tissue microarray technology. Treatment with Ob resulted in increased proliferation of CRC cell lines and involved activation of PI3K/AKT-signaling pathway. Pretreatment with Ob-R small interfering RNA or PI3K inhibitor inhibited these responses. Ob-R was significantly overexpressed in primary CRC relative to adenomas and normal colonic mucosa. In primary CRC, Ob-R significantly correlated with Ob expression, early stage and well-differentiated tumors. Intriguingly, patient with Ob-R positive tumors showed significantly better overall survival (P = 0.0098). Ob plays a critical role in CRC carcinogenesis through PI3K/AKT pathway via Ob-R. Ob-R is a prognostic marker associated with better survival.

Topics: Adenoma; Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Intestinal Mucosa; Leptin; Male; Neoplasm Staging; Obesity; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Saudi Arabia; Signal Transduction; Survival Analysis

We measured the serum adiponectin and leptin concentrations before and after successful removal of a left adrenal adenoma in a 46-year-old woman with Cushing's syndrome. The serum adiponectin level was 6.0 microg/ml before the operation and rose to 8.1 microg/ml after adrenalectomy. However, the serum leptin level was markedly high (24.8 ng/ml) before the operation and decreased to within the normal range (6.0 ng/ml) 6 months after adrenalectomy, concomitant with weight reduction and normalization of the serum cortisol level.

Topics: Adenoma; Adiponectin; Adrenal Gland Neoplasms; Adrenalectomy; Biomarkers; Blood Chemical Analysis; Cushing Syndrome; Female; Humans; Leptin; Middle Aged; Postoperative Period; Preoperative Care; Sensitivity and Specificity; Treatment Outcome

Leptin is an adipocyte-derived neurohormone, high levels of which are found in obese individuals. Leptin controls energy expenditure, acting in the brain, and regulates different processes in peripheral organs. Recent studies have suggested that leptin may be involved in cancer development and progression.. To analyse leptin expression in human colorectal cancer as well as in colorectal mucosa and colorectal adenomas.. Leptin expression was assessed by immunohistochemistry in 166 colorectal cancers, 101 samples of colorectal mucosa and 41 adenomas. Leptin concentration in colorectal cancer was correlated with selected clinicopathological features.. Immunoreactivity for leptin was observed in 51.2% (85/166) of primary colorectal cancers. In adenomas leptin expression was observed in 14.6% (6/41) of studied cases. In normal mucosa, leptin was present at low levels, except in tumour bordering areas where its concentration appeared to reflect levels in the adjacent cancer tissue. Leptin expression in colorectal cancer significantly correlated with tumour G2 grade (p = 0.002) as well as with histological type (adenocarcinoma) of tumours (p = 0.044).. Results indicate that leptin is overexpressed in human colorectal cancer, which suggests that the hormone might contribute to colorectal cancer development and progression.

Topics: Adenocarcinoma; Adenoma; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Intestinal Mucosa; Leptin; Male; Middle Aged

Obesity has been shown to be associated with an increased risk of both colorectal cancer and adenomatous polyps. One mechanism underlying this relationship may involve the growth-promoting effects of the circulating hormones associated with obesity, such as leptin. We conducted a gastroenterology clinic-based, case-control study to evaluate the relationship between circulating leptin concentrations and colorectal adenoma risk; in addition, we evaluated the relationship between leptin receptor polymorphisms and adenoma risk. Individuals with adenomas (n = 157) and colonoscopy-negative controls (n = 191), who had a clinically indicated colonoscopy, were recruited from a large health maintenance organization in the Seattle metropolitan area from 1999 to 2003. Odds ratios and 95% confidence intervals were obtained using logistic regression, adjusting for age at diagnosis, body mass index, family history of colorectal cancer, smoking history, nonsteroidal anti-inflammatory drug use, physical activity, and, among women, menopausal status and postmenopausal hormone use. Among men, those in the highest tertile of leptin concentrations had a 3.3-fold (95% confidence interval, 1.2-8.7) increased adenoma risk compared with those in the lowest tertile (P trend = 0.01). There were no associations between leptin concentrations and adenoma risk in women. There were no associations of leptin receptor genotypes or haplotypes and adenoma risk. The results of this study suggest that, in men, leptin may be associated with risk of colorectal adenomas.

Topics: Adenoma; Adult; Aged; Body Mass Index; Case-Control Studies; Colorectal Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Genotype; Haplotypes; Humans; Leptin; Male; Middle Aged; Polymorphism, Single Nucleotide; Precancerous Conditions; Receptors, Leptin; Risk Factors; Sex Factors

Correction of GH and IGF-I levels are associated with improvements in insulin secretion, cardiac performance and body composition in patients with acromegaly, but whether these parallel post-treatment levels of GH-IGF-I axis activity is undefined. We investigate whether various biochemical outcomes after transsphenoidal pituitary surgery (TSS) in these patients are associated with clinically relevant differences in cardiac performance, insulin resistance and body composition.. Cross-sectional study of consecutive patients with acromegaly admitted to the hospital between 2001 and 2002.. Forty-one patients after TSS for somatotroph pituitary adenoma and 23 patients with naive acromegaly serving as positive controls were enrolled in the study. Mean daily GH levels (mGH), IGF-I, leptin and lipid levels, glucose, insulin and GH concentrations during oral glucose tolerance test (oGTT) were measured in all study participants. Insulin resistance was measured by homeostatic model index (R(HOMA)). Body composition was assessed by dual-energy X-ray absorptiometry. Left ventricular mass index (LVM(i)) and cardiac index (C(i)) were determined by echocardiography.. We found no difference in cardiac indices, insulin resistance, body composition and leptin levels between patients with complete biochemical remission and those with inadequately controlled disease (P > 0.05 for all) after TSS. Cured patients had lower values (mean +/- SD) of cardiac index (2.2 +/- 0.7 vs. 3.0 +/- 1.0 l/min/m(2); P = 0.04) compared with naive patients. A similar decrease in LVM(i) was observed in controlled (108.4 +/- 30.0 g/m(2); P = 0.015) and inadequately controlled disease (108.8 +/- 30.7 g/m(2); P = 0.03) in comparison with naive disease (160.3 +/- 80.6 g/m(2)). Insulin resistance and leptin changed in opposite ways. In controlled and inadequately controlled disease, R(HOMA) index was lower (2.2 +/- 1.4; P = 0.001 and 3.1 +/- 2.0; P = 0.05 vs. 5.1 +/- 3.1) while leptin concentration was higher (14.9 +/- 8.7 microg/l, P = 0.004 and 12.8 +/- 7.8 microg/l, P = 0.05 vs. 7.4 +/- 3.8 microg/l) than in naive disease. In all patients, leptin correlated negatively with cardiac index (r = -0.46; P = 0.001) and IGF-I levels (r = -0.45; P < 0.001). Independent predictors of biochemical remission, based on normal IGF-I levels only, were cardiac [P = 0.04, odds ratio (OR) 0.4; 95% confidence interval (CI) 0.2-0.9] and R(HOMA) index (P = 0.009, OR 0.6; 95% CI 0.4-0.8). Similar results were obtained if the definition of cure included both normal IGF-I levels and the ability to achieve GH nadir < 1 microg/l during oGTT. Insulin resistance (P = 0.02, OR 0.6; 95% CI 0.4-0.9) and leptin level (P = 0.002, OR 1.3; 95% CI 1.1-1.6) were independent predictors of normalized mGH values.. This study shows that cardiac indices, insulin resistance and body composition were not different between patients with complete biochemical remission and those with discordant GH and IGF-I levels. It appears that even incomplete disease control after TSS can result in improvement of these clinical markers.

Topics: Absorptiometry, Photon; Acromegaly; Adenoma; Adult; Aged; Area Under Curve; Biomarkers; Blood Glucose; Body Composition; Echocardiography; Female; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Lipids; Logistic Models; Male; Middle Aged; Pituitary Neoplasms; Remission Induction; Treatment Failure

In order to investigate the effect of leptin on the secretion of rat pituitary adenoma GH3 cell and its mechanisms, we observed the effect of leptin on the growth hormone secretion, proliferation and apoptosis of GH3 cells. The results indicated that leptin at 1, 10, and 100 nmol/L could inhibit the basal growth hormone secretion of GH3 cells in a dose dependent manner (P<0.05). Short-term treatment of leptin (10 nmol/L) for 30 min, 1 and 3 h did not affect basal GH secretion. However, treatment of the GH3 cells with leptin (10 nmol/L) for 1 d or longer resulted in an inhibition of GH secretion (P<0.05). We used MTT method and flow cytometery (FCM) to study the effect of leptin on the proliferation and apoptosis of GH3 cells. We found that leptin inhibited proliferation of GH3 cells with a dose-dependent manner. And leptin reduced the proportion of cells in S phase, increased the proportion of cells in G1, and increased the proportion of GH3 cells in 2 and 4 phase. These results demonstrate that leptin inhibits the basal GH secretion of GH3 cells, which may be due to the inhibition of DNA synthesis and advanced apoptosis of GH3 cells.

Topics: Adenoma; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Growth Hormone; Leptin; Pituitary Neoplasms; Rats

Leptin, the product of the ob gene, has been suggested to increase the risk of colon cancer. However, we have shown that although leptin stimulates epithelial cell proliferation it reduces the development of carcinogen induced preneoplastic lesions in the rat colon. Here, we explored the effect of leptin in vitro on proliferation of human colon cancer cells, and in vivo on the growth of HT-29 xenografts in nude mice and the development of intestinal tumours in Apc(Min/+) mice.. Proliferation of HT-29, LoVo, Caco2, and SW 480 cells was assessed in the absence or presence of leptin (20-500 ng/ml) by 3H-thymidine incorporation and cell count. Leptin (800 microg/kg/day) or its vehicle was delivered for four weeks to nude mice, inoculated with HT-29 cells on day 0, and for six weeks to Apc(Min/+) mice.. Leptin dose dependently stimulated cell DNA synthesis and growth in all cell lines. In nude mice, leptin caused a 4.3-fold increase in plasma leptin levels compared with pair fed controls. This hyperleptinaemia, despite leptin receptor expression in tumours, did not induce significant variation in tumour volume or weight. Tumour Ki-67 index was even inhibited. In leptin treated Apc(Min/+) mice, a 2.4-fold increase in plasma leptin levels did not modify the number, size, or distribution of intestinal adenomas compared with pair fed controls.. Leptin acts as a growth factor on colon cancer cells in vitro but does not promote tumour growth in vivo in the two models tested. These findings do not support a pivotal role for hyperleptinaemia in intestinal carcinogenesis.

Topics: Adenoma; Animals; Apoptosis; Cell Division; Cell Line, Tumor; Colon; Colonic Neoplasms; DNA, Neoplasm; Genes, APC; Humans; Intestinal Mucosa; Leptin; Male; Mice; Mice, Inbred BALB C; Mice, Nude

To pursue whether leptin regulates anterior pituitary cells, we studied the ex vivo expression of several isoforms of the leptin receptor (OB-R) as well as the in vitro effects of leptin administration in human pituitary adenomas.. OB-R mRNA expression and in vitro response to leptin were studied in 39 pituitary macroadenomas.. All 4 OB-R subtypes were expressed in most adenomas. The expression was significantly more pronounced in GH-secreting adenomas as compared to non-functioning tumor cells (p < 0.05). Leptin administration in vitro did not significantly influence cell proliferation or the secretion of GH, FSH, LH or alpha-subunit.. (1) Several isoforms of the OB-R, including the signal transducing full-length receptor, are expressed in most human pituitary adenomas. (2) This expression ex vivo is not associated with significant effects of leptin in vitro.

Topics: Adenoma; Cell Division; Female; Follicle Stimulating Hormone; Gene Expression Regulation, Neoplastic; Glycoprotein Hormones, alpha Subunit; Human Growth Hormone; Humans; In Vitro Techniques; Isomerism; Leptin; Luteinizing Hormone; Male; Middle Aged; Pituitary Neoplasms; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

We immunohistochemically examined the expression of leptin in pituitary adenomas to investigate the correlation between the invasiveness of tumours and leptin expression. The subjects consisted of 79 patients with pituitary adenoma and were classified into the following groups: (1) non-functioning adenomas; (2) GH-secreting adenomas; (3) prolactinomas; (4) ACTH-secreting adenomas; (5) others (LH, FSH or TSH-secreting adenomas). Thereafter all cases were subdivided according to the size of tumour and the presence of invasion to the surrounding tissue. Among non-functioning adenomas, there was no significant difference between invasive and non-invasive non-functioning adenoma. In functioning adenomas, a significant difference in leptin expression was noted in intrasellar non-invasive adenomas compared to other adenomas. There was also a significant difference in leptin expression between non-invasive and invasive adenomas regardless of size. These results suggest that leptin has a role in the invasive potential of functioning adenomas.

Topics: Adenoma; Adult; Aged; Biomarkers, Tumor; Female; Humans; Leptin; Male; Middle Aged; Neoplasm Invasiveness; Pituitary Neoplasms; Retrospective Studies

Leptin is a circulating hormone secreted by adipose tissue and a few other tissues. It has recently been demonstrated that leptin and leptin receptors are expressed in normal and adenomatous pituitary cells. The aim of this study was to investigate the effect of recombinant human leptin on GH release from adenomatous GH-secreting cells in culture. Specimens were obtained from 10 patients with acromegaly who had undergone selective transsphenoidal adenomectomy. Cells (2 x 10(5)/well) preincubated for 24 h with leptin (10(-10)-10(-8) m) or control medium were exposed to GHRH for 2 h. The GH released into the medium was measured before and after GHRH incubation. The expression of leptin receptor isoforms was evaluated by reverse-transcriptase polymerase chain reaction (RT-PCR) in cells obtained from five adenomas.. After the first incubation, there was a slight dose-dependent leptin-induced decrease in GH released into the medium. A significant increase in GH release after GHRH was noted from cells previously exposed to leptin in comparison with cells incubated with medium alone. Expression of leptin receptors was found in two out of five GH-secreting adenomas evaluated.. Our data confirm that some, but not all, GH-secreting adenomas express leptin receptors. Leptin seems to exert both a slight inhibitory effect on spontaneous GH secretion and a stimulatory effect on GHRH-stimulated GH secretion from GH-secreting adenomatous tissue.

Topics: Adenoma; Adult; Dose-Response Relationship, Drug; Drug Synergism; Female; Gene Expression; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Leptin; Male; Middle Aged; Neoplasm Proteins; Pituitary Neoplasms; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured

Pituitary adenomas are usually sporadic, although rare familial cases have been described. Here we report two first degree female cousins with giant pituitary adenoma and overweight. Both presented with secondary amenorrhoea, occasional headache and weight gain.. In both patients clinical, morphological and genetic studies were performed. Both patients underwent surgery and post-operative medical therapy with somatostatin analogues and dopamine agonist, followed by a conventional radiotherapy course.. Clinical examination at presentation revealed an acromegaloid habitus only in the second patient. Basal and dynamic hormonal evaluation showed high serum GH and serum IGF-I values, higher in the second than in the first patient, and a mild hyperprolactinaemia only in the first patient. On optical and electron microscopy, both tumours were oncocytic adenomas, immunopositive for GH in the first patient and GH/prolactin in the second. The genetic analysis for germ-line mutations of the multiple endocrine neoplasia type 1 gene was negative. Two years after radiotherapy a remarkable shrinkage of both tumours was observed, whereas the overweight worsened in both patients, accompanied by high plasma leptin values.. To our knowledge, this is the first report of familial pituitary adenomas including one case of a clinically silent GH-secreting adenoma. In addition, it provides further evidence that familial pituitary tumours can occur as a multiple endocrine neoplasia type 1 unrelated disease.

Topics: Adenoma; Adult; Amenorrhea; Anthropometry; DNA Mutational Analysis; Family Health; Female; Genetic Testing; Headache; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Magnetic Resonance Imaging; Microscopy, Electron; Multiple Endocrine Neoplasia Type 1; Mutation; Pituitary Neoplasms; Prolactin; Weight Gain

Leptin is the protein product of the obese gene, known to play an important role in body energy balance. The leptin receptor exists in numerous isoforms, the long isoform being the major form involved in signal transduction. Leptin expression has recently been demonstrated in the human pituitary, both in normal tissue and in pituitary adenomas. The long isoform of the leptin receptor has also been shown to be present in pituitary adenomas; however, contrasting results have been obtained regarding its expression in the normal human pituitary.. The aim of this study was (i) to investigate the presence and pattern of distribution of leptin mRNA and the long isoform of its receptor mRNA in the normal pituitary and in different types of pituitary adenomas with RT-PCR; (ii) to study leptin secretion from human pituitary tumours in culture and (iii) to assess in vitro pituitary hormone release following stimulation with human leptin.. Leptin receptor long isoform expression was detected in 2/4 GH-secreting adenomas, 12/17 non-functioning adenomas, 5/9 ACTH-secreting adenomas, 1/2 prolactinomas, 2/2 FSH-secreting adenomas and 5/5 normal pituitaries. The receptor long isoform did not segregate with any particular tumour type, and varying levels of expression were detected between the tissues studied. Leptin mRNA was detected at a low level of expression in 2/7 GH-secreting adenomas, 9/14 non-functioning adenomas, 2/3 ACTH-secreting adenomas, 1/3 prolactinomas and 1/3 FSH-secreting adenomas. We were unable to detect leptin mRNA in any of the five normal pituitaries removed at autopsy; however, immunostaining of a non-tumorous pituitary adjacent to an adenoma removed at transsphenoidal surgery showed scattered leptin positive cells. Culture of pituitary adenomas showed that 16/47 released leptin into the incubation media. Leptin release did not correlate with tumour type or with any of the other pituitary hormones released. In vitro leptin stimulation of pituitary tumours caused stimulation of FSH and alpha-subunit secretion from a non-functioning adenoma and TSH secretion from a somatotroph adenoma.. We conclude that not only is leptin stored within the pituitary, but it may also be released from pituitary cells and modulate other pituitary hormone secretion. Pituitary leptin may therefore be a novel paracrine regulator of pituitary function.

Topics: Adenoma; Adrenocorticotropic Hormone; Analysis of Variance; Carrier Proteins; Growth Hormone; Humans; Leptin; Paracrine Communication; Pituitary Gland; Pituitary Neoplasms; Prolactinoma; Protein Isoforms; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; RNA, Messenger; Statistics, Nonparametric; Stimulation, Chemical; Tumor Cells, Cultured

The aim of this study was to assess human intracranial tumours for their gene expression pattern of the vasoactive peptide adrenomedullin (AM), its receptor (AM-R) and leptin, which exerts multiple biological effects including proliferation and angiogenesis via the leptin receptor (OB-Rb). Gene activity of neuropeptide Y (NPY) was monitored additionally. We investigated whether there was a characteristic gene expression pattern of AM and leptin in different intracranial tumours, depending on their proliferation activity and biological behaviour. We investigated 35 non-functioning pituitary adenomas (including eight null cell, four silent plurihormonal, 23 silent gonadotroph adenomas), seven somatotropinomas, seven prolactinomas, eight meningiomas, five astrocytomas, two glioblastoma multiformes and unaffected temporal lobe (n = 8). Quantitative reverse transcriptase-polymerase chain reaction (TaqMan RT-PCR) was performed. AM mRNA was detectable in all tumour specimens. AM/GAPDH (glyceraldehyde-3-phosphate dehydrogenase) ratio was significantly higher in somatotropinomas, as was AM/CD31 ratio in prolactinomas, compared with inactive adenomas (P < 0.05). AM-R mRNA was found in all tumour subgroups in small quantities but, in general, higher in tumours than in temporal lobe tissue, respectively. AM-R/CD31 ratio was significantly higher in prolactinomas than in inactive adenomas (P < 0.05). Leptin was detectable in very low quantities in each subgroup. OB-Rb gene expression was found in all tumour subgroups, OB-Rb/GAPDH ratio was highest for meningiomas (P < 0.0001, compared with temporal lobe). NPY mRNA was detectable in temporal lobe in higher quantities than in tumours (P < 0.0001), and almost undetectable in prolactinomas and astrocytomas. Our data demonstrate that AM and AM-R, NPY, as well as leptin and OB-Rb, are expressed in various intracranial tumours in humans but their particular function has to be elucidated further. At present, there is no evidence for a cross-talk on transcriptional level between the peptidergic vasodilative system AM and the putative angiogenic and proliferation affecting factor leptin.

Topics: Adenoma; Adrenomedullin; Adult; Aged; Brain Neoplasms; Carrier Proteins; Female; Gene Expression; Hormones; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Neuropeptides; Peptides; Pituitary Neoplasms; Receptors, Adrenomedullin; Receptors, Cell Surface; Receptors, Leptin; Receptors, Peptide

Topics: Adenoma; Animals; Cyclic GMP; Female; Humans; Leptin; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Pituitary Hormones; Pituitary Neoplasms; Rats

Leptin is a key mediator in the maintenance of neuroendocrine homeostasis. Recently, leptin and leptin receptor expression were demonstrated in non-tumorous and adenomatous human pituitaries. This study was performed to determine the subcellular localization of leptin in human adenohypophyses (n = 3) and in various types of pituitary adenoma (n = 16). Immunoelectron microscopy showed leptin immunolabeling in most hormone-producing cells of the human non-tumorous adenohypophysis, but not in stellate cells. Labeling was noted over secretory granules. Immunocytochemistry using double labeling revealed leptin expression in GH-, ACTH-, TSH-, and FSH/LH-containing cells but not in PRL cells. The percentage of immunopositive cells and the intensity of immunostaining varied considerably among the various cell types. Immunoelectron microscopy with double gold labeling showed co-localization of leptin and adenohypophysial hormones in the same secretory granules. Among pituitary tumors, leptin immunolabeling was evident only in corticotroph adenomas. Compared to non-tumorous corticotrophs, leptin immunoexpression was less abundant in corticotroph adenomas. The presence of leptin and adenohypophysial hormones in the same secretory granules suggests that leptin is secreted concomitantly with various adenohypophysial hormones and that its release is under the control of hypothalamic stimulating and inhibiting hormones.

Topics: Adenoma; Humans; Leptin; Microscopy, Immunoelectron; Pituitary Gland, Anterior; Pituitary Neoplasms; Subcellular Fractions

Leptin is an adipocyte-derived cytokine with many functions including signaling the status of body energy stores through activation of the leptin receptor (OBR). Activation of the long form of OB-R (OB-Rb) results in JAK2 phosphorylation, activation of STATs, and subsequent gene expression. Activated STAT3 induces SOCS-3 expression in some cell types, which in turn down-regulates the JAK/STAT pathway. Although both leptin and OB-R are expressed in pituitary cells, the mechanism of signal transduction and its regulation in this organ has not been studied extensively. In these experiments we show that leptin reduces proliferation in a human pituitary cell line (HP75) and also increased apoptosis in these cells. Leptin also increased SOCS-3 mRNA and protein expression and tyrosine-phosphorylation in the HP75 human pituitary cell line. These findings suggest that SOCS-3 plays an important role in the inhibition of proximal leptin signal transduction in the anterior pituitary.

Topics: Adenoma; Antigens, Polyomavirus Transforming; Apoptosis; Carrier Proteins; Cell Cycle Proteins; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; DNA-Binding Proteins; Gene Expression; Humans; Leptin; Milk Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Phosphorylation; Phosphotyrosine; Pituitary Gland; Pituitary Neoplasms; Proteins; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; Repressor Proteins; RNA, Messenger; Signal Transduction; STAT1 Transcription Factor; STAT3 Transcription Factor; STAT5 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Trans-Activators; Transcription Factors; Transfection; Tumor Cells, Cultured; Tumor Suppressor Proteins

Leptin, a hormone mainly secreted from adipose tissue, communicates a metabolic signal to the adrenal gland. Ob-Receptor (Ob-R) expression was reported in rat, mice and human adrenal glands. This study intended to investigate possible differences in the Ob-R expression and distribution of Ob-R protein in human adrenal tumors as compared to normal adrenal tissue. Proliferative effects of leptin were analyzed in the human adrenocortical carcinoma cell line (NCI-H295). The full length Ob-R mRNA and the isoforms B219.1 and B219.3 could be demonstrated by RT-PCR in all adrenal tumors (n=8), the tumor cell line (NCI-H295) and normal tissue. In contrast the Ob-R isoform B219.2 was absent in the carcinoma cell line and in most of the adrenal tumors (n=5), whereas it was present in normal adrenals. The Ob-R protein could be demonstrated in benign and malignant adrenocortical tumors. Pheochromocytomas showed only a weak immunostaining with the human Ob-R antibody. Human leptin did not affect the proliferation or variability of adrenal tumor cells as demonstrated by [3H]-thymidine assay and WST-1 test. In conclusion, although functional leptin receptors are expressed in human adrenal tumors, leptin does not regulate tumor cell proliferation.

Topics: Adenoma; Adrenal Cortex Neoplasms; Adrenal Gland Neoplasms; Adrenal Glands; Adult; Carrier Proteins; Cell Division; Cell Survival; Gene Expression; Humans; Immunohistochemistry; Leptin; Middle Aged; Pheochromocytoma; Proteins; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Leptin, the obese (ob) gene product, is an adipocyte-derived satiety factor that is involved in the regulation of food ingestion and body weight. To investigate glucocorticoid regulation of leptin synthesis and secretion in humans, we measured plasma leptin levels in patients with Cushing's syndrome with adrenal or pituitary adenoma and in patients with iatrogenic Cushing's syndrome. Plasma leptin levels in patients with Cushing's syndrome were significantly elevated compared to those in nonobese healthy subjects and obese subjects without any metabolic or endocrine diseases at a given percentage of body fat by analysis of covariance. In patients with adrenal or pituitary adenoma, after the tumor resection, plasma leptin levels were reduced, with a concurrent decrease in plasma cortisol levels. With no significant changes in body weight, plasma leptin levels were also elevated significantly in lean healthy volunteers 24 h after the administration of 1 mg dexamethasone. Dexamethasone potently induced ob gene expression and leptin secretion in the organ culture of human adipose tissue. The data demonstrate that glucocorticoids act, at least in part, directly on the adipose tissue and increase leptin synthesis and secretion in humans.

Topics: Adenoma; Adipose Tissue; Adolescent; Adrenal Gland Neoplasms; Adult; Cushing Syndrome; Dexamethasone; Female; Gene Expression; Glucocorticoids; Humans; Hydrocortisone; Leptin; Male; Middle Aged; Organ Culture Techniques; Pituitary Neoplasms; Protein Biosynthesis; Proteins

In the present study, we characterized the changes in plasma leptin levels in patients with pituitary Cushing's disease and in age- and sex-matched controls. Plasma levels of ACTH, cortisol, and leptin were measured before and after iv administration of ovine CRH in controls once and in patients twice (while they had active hypercortisolism and 10 days after successful surgery). Cushing's patients had elevated body mass indexes (34 +/- 1.9 vs. 22.9 +/- 0.8) and plasma leptin levels (35.6 +/- 3.4 vs. 9.2 +/- 1.9 ng/mL) compared to controls, which remained unchanged 10 days after successful transsphenoidal surgery and directly proportional to the body mass index. Plasma leptin levels were not affected by CRH infusion in either the controls or the patients despite clear-cut elevations in plasma ACTH and cortisol. These findings suggest that although acute changes in plasma cortisol do not affect plasma leptin, chronic hypercortisolism results in elevated leptin levels, probably by causing visceral obesity.

Topics: Adenoma; Adrenocorticotropic Hormone; Adult; Body Mass Index; Corticotropin-Releasing Hormone; Cushing Syndrome; Female; Humans; Hydrocortisone; Leptin; Male; Middle Aged; Obesity; Pituitary Neoplasms; Proteins

To study a potential alteration of hypothalamic centers involved in the negative feedback action of leptin on body weight, serum leptin levels were measured in relation to BMI in 18 patients following surgery for a hypothalamic craniopharyngioma (Ctx), and were compared to levels found in 21 patients operated for a pituitary adenoma (Ptx) or in healthy control subjects. All subjects with Ptx received rhGH replacement therapy (0.5 to 2 IU/m2/d), and serum leptin levels were followed in 3 months intervals over 24 months. Serum leptin levels in patients with Ptx were comparable to controls, whereas 7 of the 18 patients with Ctx had higher than expected concentrations for their BMI. GH treatment in Ptx subjects did not alter serum leptin levels. In 5 Ctx patients where preoperative samples were available, weight gain in parallel to an increase in serum leptin levels was observed but only minimal changes in 4 others. Our data support the role of leptin as an important marker of body weight. The rapid increase in serum leptin levels observed in some Ctx subjects suggests that early postoperative measurement of serum leptin levels may help to identify patients at risk of weight gain following hypothalamic destruction.

Topics: Adenoma; Adolescent; Adult; Body Mass Index; Child; Child, Preschool; Craniopharyngioma; Female; Humans; Hypothalamic Neoplasms; Leptin; Male; Middle Aged; Pituitary Neoplasms; Proteins; Sex Characteristics; Weight Gain