leptin and Hyperplasia

Leptin has received much attention since its cloning in 1994. Initially, leptin research centered on satiety, energy balance and sympathetic activation. However, hyperleptinemia has since been identified as an independent risk factor for various cardiovascular pathologies including atherosclerotic coronary artery disease. Over the last decade, multiple studies have implicated leptin as an important mediator in endothelial dysfunction and neointimal hyperplasia, both key steps in the evolution of atherosclerotic vascular changes. Additionally, more recent evidence indicates that paracrine leptin release from perivascular adipose tissue (PVAT) has deleterious effects on the underlying endothelium and vascular smooth muscle cells (SMC), including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, SMC proliferation and the role of PVAT-derived leptin with an emphasis on the coronary circulation and discussions of currently proposed molecular mechanisms of PVAT-mediated coronary endothelial dysfunction and neointimal hyperplasia.

Topics: Adipose Tissue; Animals; Atherosclerosis; Cardiovascular Agents; Down-Regulation; Endothelium, Vascular; Humans; Hyperplasia; Leptin; Models, Cardiovascular; Molecular Targeted Therapy; Systemic Vasculitis; Tunica Intima; Up-Regulation

Fundectomy, shown as an alternative to restrictive techniques, causes absorption restriction and metabolic changes. This study aimed to examine the histopathological changes caused by the fundectomy as a technique applied to rats by hormones that affect stomach and obesity metabolism and its effect on weight loss.. 2randomly selected Winstar-Hannover rat groups were evaluated by measuring their pre-and postoperative weights and biochemically measuring Gastrin, Ghrelin, and Leptin levels on day 30. After sacrification, the stomachs were taken for histopathological examination.. Significant weight loss was observed in the fundectomy group in the 1stmonth postoperatively. Biochemically, Gastrin means in the fundectomy group were statistically significantly higher than in the control group. The mean Ghrelin and Leptin levels of the Fundectomy Group were statistically significantly lower (p=0.005). Immunohistochemically, Gastrin means ™at the antrum and proximal stomach parts of the Fundectomy Group were significantly higher than in the control group. As Ghrelin, a significant decrease was observed in all 3regions of the Fundectomy Group compared to the control group. Leptin results were significantly lower at the antrum and proximal stomach parts of the Fundectomy Group. Histopathologically, in the Fundectomy Group, cystic glandular hyperplasia was moderate at the proximal stomach, foveolar hyperplasia was mild at the antrum, fibrosis was moderate at the antrum and corpus, and high at the proximal stomach.. Fundectomy is an effective method in terms of weight loss. This animal experiment, conducted as a pilot study, will be an essential step in elucidating metabolic and histopathological changes.. Bariatric surgery, Fundectomy, Obesity.. La resezione del fondo gastrico, indicata come alternativa alle tecniche restrittive, provoca restrizione dell’assorbimento e alterazioni metaboliche. Questo studio mirava a esaminare i cambiamenti istopatologici causati da questo intervento eseguito su ratti ad opera di ormoni che influenzano il metabolismo dello stomaco e dell’obesità e il suo effetto sulla perdita di peso. Sono stati utilizzati 2 Gruppi di ratti Winstar-Hannover, selezionati casualmente, valutando il loro peso pre e postoperatorio e misurando biochimicamente i livelli di gastrina, grelina e leptina al giorno 30. Dopo il sacrificio, gli stomaci sono stati sottoposti ad esame istopatologico. RISULTATI: È stata osservata nel 1° mese dopo l’intervento una significativa perdita di peso nel gruppo dei resecati del fondo gastrico. Dal punto di vista biochimico, i livelli medi della Gastrina è risultato statisticamente e significativamente più elevato nel gruppo dei gastroresecati rispetto al gruppo di controllo. I livelli medi di grelina e leptina sono risultati statisticamente e significativamente più bassi (p=0,005) nel gruppo dei gastroresecati. Dal punto di vista immuno-istochimico i livelli medi della Gastrina sono risultati significativamente più elevati nelle parti dell’antro e dello stomaco prossimale nel gruppo dei gastro-resecati rispetto al gruppo di controllo. Per quanto riguarda la Grelina, è stata osservata una diminuzione significativa in tutte e 3 le regioni del gruppo della fundectomia rispetto al gruppo di controllo. I risultati della leptina sono risultati significativamente più bassi nelle parti dell’antro e dello stomaco prossimale del gruppo dei fundectomizzati. Dal punto di vista istologico nel gruppo della fundectomia, l’iperplasia ghiandolare cistica era moderata nello stomaco prossimale, l’iperplasia foveolare era lieve all’antro, la fibrosi era moderata all’antro e al corpo ed elevata nello stomaco prossimale. CONCLUSIONE: la fundectomia si è dimostrata un metodo efficace ai fini della riduzione del peso. Questo studio sperimentale sugli animali, condotto come studio pilota, potrà rappresentare un passaggio essenziale per chiarire i cambiamenti metabolici e istopatologici della resezione del fondo gastrico.

Topics: Animals; Gastrins; Ghrelin; Hyperplasia; Leptin; Obesity; Pilot Projects; Rats; Weight Loss

Leptin is an adipokine with roles in food intake and energy metabolism through its actions on neurons in the hypothalamus. The role of leptin in obesity and cardiovascular disorders is well documented. However, its influence on liver conditions such as cholestasis is poorly understood. The effects of exogenous leptin and leptin-neutralizing antibody on biliary hyperplasia, hepatic fibrosis, and inflammation in the multidrug resistance protein 2 knockout (Mdr2KO) mouse model of cholestasis were assessed by quantifying markers specific for cholangiocytes, activated hepatic stellate cells (HSCs), and cytokines. Serum and hepatic leptin were increased in Mdr2KO mice compared with FVB/NJ (FVBN) controls, and exogenous leptin enhanced biliary hyperplasia and liver fibrosis in Mdr2KO and FVBN mice. Leptin administration increased hepatic expression of C-C motif chemokine ligand 2 and IL-6 in Mdr2KO mice. In contrast, leptin-neutralizing antibody reduced intrahepatic bile duct mass and decreased HSC activation in Mdr2KO mice compared with FVBN controls. Sex-related differences were noted, with female Mdr2KO mice having more leptin than males. In cholangiocytes and LX2 cells in vitro, leptin increased phosphorylated Akt and stimulated cell proliferation. Leptin receptor siRNA and inhibitors of Akt phosphorylation impaired leptin-induced cell proliferation and proinflammatory cytokines. The current data suggest that leptin is abnormally increased in cholestatic mice, and excess leptin increases ductular reaction, hepatic fibrosis, and inflammation via leptin receptor-mediated phosphorylation of Akt in cholangiocytes and HSCs.

Topics: Animals; Antibodies, Neutralizing; Cholestasis; Cytokines; Disease Models, Animal; Female; Hepatic Stellate Cells; Hyperplasia; Inflammation; Leptin; Liver; Liver Cirrhosis; Male; Mice; Mice, Knockout; Proto-Oncogene Proteins c-akt; Receptors, Leptin

To observe fat tissue and the expression of adipokines in rheumatic heart valves and explore the possible role of fat tissue and adipokines in the pathology of rheumatic heart disease (RHD).. In this retrospective study, a total of 29 patients who received mitral valve replacement surgery were included. The study group consisted of 25 patients with RHD while the control group consisted of 4 patients with secondary mitral insufficiency caused by coronary heart disease (CAD). The clinical data of the patients including medical history, age, body mass index (BMI), fasting blood glucose (FBG), total triglycerides (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein(a) [apo(a)], apolipoprotein(b) [apo(b)] were collected and compared. Cardiac ultrasonography was used to assess valve conditions before surgery. The removed valves were collected. The hematoxylin-eosin (HE) staining, oil-red O staining, and Masson's trichrome staining were adopted to evaluate the histological changes in the mitral valve. Immunohistochemical (IMC) staining was performed to evaluate the expression of adiponectin, leptin, and chemerin.. There was no significant difference in general information and blood lipid levels between the two groups (all p > .05). Preoperative ultrasonography showed adipose tissue in the mitral valve of RHD patients. In the study group, rheumatic mitral valve samples showed thickening, adherence at the junction of the leaflets, calcification, and yellowish or fat mass by naked observation. The HE staining showed that there was calcification, inflammatory cell infiltration, fibrous tissue arranged disorder, and neovascularization. The oil-red O staining suggested fatty infiltration. Masson's trichrome staining suggested disorderly arrangement of collagen fiber and elastic fiber in rheumatic lesions, and the lesions were dominated by collagen fiber hyperplasia and less elastic fiber hyperplasia. The results of IMC indicated that chemerin was not expressed in valves of the control group. Most of the valve samples from the study group also did not show leptin and the leptin was seen in only a few rheumatic mitral valves with vascular hyperplasia. Adiponectin was not found in the valves of the study group and the control group.. Adipose tissue in the rheumatic mitral valve could be observed by ultrasound. The fat mass and adipokines existed in rheumatic mitral valves, the adipocytokine chemerin is involved in the progression of the pathology in RHD.

Topics: Adipokines; Adipose Tissue; Cholesterol; Collagen; Heart Valve Diseases; Humans; Hyperplasia; Leptin; Mitral Valve; Retrospective Studies; Rheumatic Heart Disease

Topics: Adenocarcinoma; Animals; Carcinogenesis; Cell Proliferation; Gastric Mucosa; Hyperplasia; Leptin; Male; Methylnitronitrosoguanidine; Rats; Rats, Sprague-Dawley; Stomach; Stomach Neoplasms

Obesity and prostate cancer are related, but the causal relationship remains unknown. The aim of the study was to compare concentrations of leptin, adiponectin and chemerin in patients with prostate cancer and benign prostate hyperplasia and to examine associations of the adipokines with the grade of prostate cancer, interleukin-6 (IL-6), insulin resistance and anthropometric and metabolic variables.. The study group consisted of 140 men divided into two groups: I- prostate cancer (n=74) and II- with benign hyperplasia (n=66). Serum leptin, adiponectin, chemerin, IL-6 and metabolic profile were measured. Considering histological differentiation prostate cancer patients were divided into 3 subgroups: well differentiated (Gleason score ≤ 6), moderately differentiated subgroup (Gleason 7), and poorly differentiated (Gleason ≥8).. There were no differences between groups in BMI, waist circumference, HOMA-I, serum levels of total cholesterol, glucose, triglycerides, adiponectin, leptin and chemerin. However, the concentrations of PSA, leptin-to-adiponectin ratio and IL-6 were significantly higher in cancer group compared with benign hyperplasia group. In the poorly differentiated cancer subgroup, subjects had higher PSA, leptin, chemerin, IL-6 and triglycerides concentrations. Overweight and obese men with prostate cancer were more likely to have moderately or poorly differentiated cancer than those with normal BMI. In the all men serum adiponectin was significantly correlated with HOMA-I, BMI, glucose, triglycerides, cHDL. There were significant correlations between leptin and BMI, HOMA-I, waist, glucose, triglycerides and cHDL. Among all the participants we observed associations between chemerin and waist as well as triglycerides. In prostate cancer patients chemerin correlated with IL-6 and leptin. We measured significant positive correlations between Gleason score and chemerin and leptin concentrations. There was a positive correlation between adiponectin and PSA levels in all men, as well as in cancer group.. Leptin-to-adiponectin ratio and IL-6 were elevated in men with prostate cancer. Leptin, chemerin and IL-6 were associated with Gleason score. The relationships between leptin, chemerin and IL-6 were dependent on each other. Overweight and obese men had a higher Gleason score.

Topics: Adipokines; Adiponectin; Aged; Chemokines; Humans; Hyperplasia; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Prostate; Prostatic Neoplasms

Our aim was to evaluate whether chronic administration of CAF affects the uterus and induces the morphological and molecular changes associated with endometrial hyperplasia. Female Wistar rats exposed to CAF from weaning for 20 weeks displayed increased energy intake, body weight and fat depots, but did not develop metabolic syndrome. The adult uteri showed an increase in glandular volume fraction and stromal area. The epithelial proliferation rate and protein expression of oestrogen receptor alpha (ERα) were also increased. The CAF diet enhanced leptin serum levels and the long form of leptin receptor (Ob-Rb) mRNA expression in the uterus. No changes were detected in either insulin serum levels or those of insulin growth factor I (IGF-I) mRNA expression. However the levels of IGF-I receptor (IGF-IR) mRNA were lower in CAF-fed animals. Overall, the results indicate that our rat model of the CAF diet produces morphological and molecular changes associated with uterine hyperplasia and could predispose to endometrial carcinogenesis.

Topics: Adipose Tissue; Animals; Body Weight; Cell Proliferation; Diet; Endocrine System; Endpoint Determination; Estrogen Receptor alpha; Feeding Behavior; Female; Hormones; Hyperplasia; Leptin; Rats, Wistar; Uterus

MFN2 encodes mitofusin 2, a membrane-bound mediator of mitochondrial membrane fusion and inter-organelle communication. MFN2 mutations cause axonal neuropathy, with associated lipodystrophy only occasionally noted, however homozygosity for the p.Arg707Trp mutation was recently associated with upper body adipose overgrowth. We describe similar massive adipose overgrowth with suppressed leptin expression in four further patients with biallelic MFN2 mutations and at least one p.Arg707Trp allele. Overgrown tissue was composed of normal-sized, UCP1-negative unilocular adipocytes, with mitochondrial network fragmentation, disorganised cristae, and increased autophagosomes. There was strong transcriptional evidence of mitochondrial stress signalling, increased protein synthesis, and suppression of signatures of cell death in affected tissue, whereas mitochondrial morphology and gene expression were normal in skin fibroblasts. These findings suggest that specific MFN2 mutations cause tissue-selective mitochondrial dysfunction with increased adipocyte proliferation and survival, confirm a novel form of excess adiposity with paradoxical suppression of leptin expression, and suggest potential targeted therapies.

Topics: Adipose Tissue; GTP Phosphohydrolases; Human Body; Humans; Hyperplasia; Leptin; Mitochondria; Mitochondrial Proteins; Mutation

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

The adipocytokine leptin is an independent cardiovascular risk factor and exerts proatherogenic effect. Pre-existing vascular disease is an important cause of arteriovenous fistula (AVF) maturation failure. We explored the association between serum leptin, pre-existing vascular disease, and AVF maturation failure in incident hemodialysis patients.. Vein samples from 62 patients were collected at the time of AVF creation. Pre-existing vascular disease was evaluated with histologic changes and immunohistochemical characteristics of cellular phenotypes in intima. AVF maturation failure was defined as an AVF that could not be used successfully by the third month after its creation.. The prevalence of body mass index ≥30 kg/m. Obesity-related higher fistula maturation failure rate may be partly mediated by higher leptin level-associated pre-existing vascular diseases in end-stage renal disease patients. Decreased expression of leptin receptor may be related to this association.

Topics: Adult; Aged; Aged, 80 and over; Arteriovenous Shunt, Surgical; Biomarkers; Body Mass Index; Female; Humans; Hyperplasia; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Obesity; Prospective Studies; Receptors, Leptin; Renal Dialysis; Republic of Korea; Risk Factors; Treatment Failure; Up-Regulation; Vascular Diseases; Veins

Adipose tissue (AT) expansion is the result of two processes: hyperplasia and hypertrophy; and both, directly or indirectly, depend on the adipogenic potential of adipocyte precursor cells (APCs). Glucocorticoids (GCs) have a potent stimulatory effect on terminal adipogenesis; while their effects on early stages of adipogenesis are largely unknown. In the present work, we study, in a model of high GC levels, the adipogenic potential of APCs from retroperitoneal AT (RPAT) and its relationship with RPAT mass expansion. We employed a model of hyper-adiposity (30- and 60-day-old rats) due to high endogenous GC levels induced by neonatal treatment with l-monosodium glutamate (MSG). We found that the RPAT APCs from 30-day-old MSG rats showed an increased adipogenic capacity, depending on the APCs' competency, but not in their number. Analyses of RPAT adipocyte diameter revealed an increase in cell size, regardless of the rat age, indicating the prevalence of a hypertrophic process. Moreover, functional RPAT alterations worsened in 60-day-old rats, suggesting that the hyperplastic AT expansion found in 30-day-old animals might have a protective role. We conclude that GCs chronic excess affects APCs' adipogenic capacity, modifying their competency. This change would modulate the hyperplastic/hypertrophic balance determining healthy or unhealthy RPAT expansion and, therefore, its functionality.

Topics: Adipocytes; Adipogenesis; Adiposity; Animals; Cell Differentiation; Cell Proliferation; Cells, Cultured; Corticosterone; Disease Models, Animal; Glucocorticoids; Hyperplasia; Hypertrophy; Insulin; Intra-Abdominal Fat; Leptin; Male; Malonates; Obesity; Rats; Rats, Sprague-Dawley

The purpose of this study was to search for the effects of adenotonsillectomy (A&T) on height, weight, and body mass index (BMI), as well as changes in ghrelin, leptin, and insulin-like growth factor 1 (IGF-1) levels in children with adenotonsillar hypertrophy (ATH)-related sleep-disordered breathing (SDB).. A study cohort of 39 children clinically diagnosed with ATH-related SDB was included in this study. Twenty-three healthy children were included as controls. Height and weight standard deviation scores (SDS) and ghrelin, leptin, and IGF-1 levels of the controls were determined once; in the study group, they were determined preoperatively and in the third month postoperatively.. Preoperative IGF-1 (ng/mL) and ghrelin (pg/mL) levels were significantly higher in the patients than in the controls (322.51±113.10 vs. 256.96±176.73, p<0.05 and 106.08±9.75 vs. 80.11±28.50, p<0.001, respectively). The preoperative height and weight SDS values of the patients were lower than those of the controls (-0.67±1.36 vs. 0.13±1.13, p<0.05 and -0.38±1.35 vs. -0.20±1.29, respectively). The patients' postoperative height and weight SDS values were significantly higher than their preoperative values (-0.05±1.08 vs. -0.67±1.36, p<0.0001 and 0.00±1.28 vs. -0.38±1.35, p<0.0001, respectively). The mean postoperative IGF-1 levels also were significantly higher than preoperative levels (386.05±130.06 vs. 322.51±113.10, p<0.05, respectively).. Plasma IGF-1 levels are lower in malnourished children, and plasma ghrelin levels are decreased after acute oral food intake and are increased in cachexia and fasting. Therefore, increased serum IGF-1 levels, height and weight SDS values, and decreased ghrelin levels detected postoperatively are useful parameters that help to monitor the development of children with adequate oral intakes.

Topics: Adenoidectomy; Adenoids; Body Height; Child; Child, Preschool; Female; Ghrelin; Humans; Hyperplasia; Hypertrophy; Insulin-Like Growth Factor I; Leptin; Male; Palatine Tonsil; Tonsillectomy

It is well established that the excessive consumption of a high-fat diet (HFD) results in overweight, obesity and an increase in leptin concentrations, which triggers a chronic inflammatory condition that is associated with a high white blood cell count. Two-month-old male Wistar rats were fed a control (CON) diet or an HFD for 12 weeks. After this period, hemogram, myelogram and biochemical parameters were evaluated along with the cell cycle and the percentage of CD34(+) cells in the bone marrow as well as cell proliferation and differentiation assays and the production of stem cell factor, interleukin 3 (IL-3), granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF). The HFD animals exhibited leukocytosis and neutrophilia with increased C-reactive protein, leptin, cholesterol and triglyceride concentrations. In the HFD group, the bone marrow revealed myeloid hyperplasia, especially of the granulocytic compartment with a higher percentage of CD34(+) cells and a higher percentage of cells in the G2/S/M cell cycle phases. In addition, the HFD bone marrow cells had a higher capacity to proliferate and differentiate into granulocytic cells in an in vitro system and a higher capacity to produce IL-3 and G-CSF. These data led us to infer that the HFD induces leukocytosis and neutrophilia suggesting alterations in hematopoiesis system modulation.

Topics: Animals; Bone Marrow Cells; C-Reactive Protein; Cells, Cultured; Cholesterol; Diet, High-Fat; Dietary Fats; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hyperplasia; In Vitro Techniques; Interleukin-3; Leptin; Leukocytosis; Male; Models, Animal; Neutrophils; Rats; Rats, Wistar; Stem Cell Factor; Triglycerides

Leptin and its receptor (ObR) expression were investigated by immunohistochemistry in normal, hyperplastic and neoplastic canine mammary tissues and related to clinical-pathological features. Leptin expression was detected in healthy mammary tissues, adenosis and in benign mammary tumours and was lower in ductal hyperplasias and malignant tumours. A high percentage of ObR-positive cells were present in adenosis, benign tumours and in complex carcinomas, while ObR expression was lower in healthy mammary tissues, in ductal hyperplasias and in a large part of invasive mammary carcinomas. Our data demonstrated that cancer cells expressed at low level leptin and ObR in canine mammary tumours with a more aggressive behaviour, as well as in lymph node metastases. Consequently, leptin and ObR expressions in this species resulted to be not associated with a reduced overall survival.

Topics: Animals; Dog Diseases; Dogs; Female; Hyperplasia; Leptin; Mammary Glands, Animal; Mammary Neoplasms, Animal; Receptors, Leptin

Despite the use of the sirolimus (rapamycin) drug-eluting coronary stent, diabetics are at increased risk of developing in-stent restenosis for unclear reasons. Hyperleptinemia, which often coexists with diabetes and metabolic syndrome, is an independent risk factor for progression of coronary artery disease. It has not been determined whether elevated circulating leptin decreases the efficacy of the sirolimus drug-eluting stent in inhibiting neointimal hyperplasia, the process underlying restenosis after stenting. Here we show that leptin activates the mammalian target of rapamycin (mTOR) signaling pathway in primary murine vascular smooth muscle cells (VSMC) and stimulates VSMC proliferation in a PI3K-dependent fashion. Exogenous leptin, administered at levels comparable to those found in obese humans, promotes neointimal VSMC hyperplasia in a murine femoral artery wire injury model. Leptin significantly increases the dose of the mTOR inhibitor sirolimus that is required for effective inhibition of neointimal formation. Combination therapy with LY294002, a PI3K inhibitor, and sirolimus effectively inhibits leptin-enhanced neointimal hyperplasia. These data show that, in the setting of hyperleptinemia, higher doses of an mTOR inhibitor, or combination therapy with mTOR and PI3K inhibitors, inhibits neointimal hyperplasia after arterial injury. These studies may explain the higher rates of restenosis observed in diabetics treated with a sirolimus-eluting coronary stent and suggest a potential novel therapeutic approach for inhibiting in-stent restenosis in such patients.

Topics: Animals; Antibiotics, Antineoplastic; Cells, Cultured; Female; Humans; Hyperplasia; Leptin; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinases; Receptors, Leptin; Signal Transduction; Sirolimus; Stents; TOR Serine-Threonine Kinases; Tunica Intima

Hyperandrogenism in postmenopausal women is due to ovarian hyperthecosis or an androgen-secreting ovarian/adrenal tumor. Making the correct diagnosis might be complicated due to the possible existence of an adrenal neoplasm secreting testosterone only, ectopic ovarian tissue or ectopic luteinizing hormone/human chorionic gonadotropin receptors in the adrenals, as well as the relatively low sensitivity of imaging techniques (computed tomography, magnetic resonance imaging) and vein catheterization for this type of pathology. We present the case of an obese postmenopausal woman with metabolic syndrome, hyperandrogenism (high testosterone levels, suppressed gonadotropins), adrenal macronodular hyperplasia and Leydig-cell ovarian tumor. At presentation she had low leptin levels despite high body fat content. After a catheter study left adrenalectomy was carried out but hyperandrogenism persisted. Then, bilateral oophorectomy with hysterectomy was performed and a small Leydig-cell tumor was found in the left ovary. Postoperatively, testosterone and gonadotropin levels were normal (postmenopausal) and leptin level became elevated without change in body mass index or body fat content. In conclusion, we speculate that low leptin levels in obese hyperandrogenic women might be a marker for androgen-secreting tumors.

Topics: Adrenal Glands; Alopecia; Biomarkers; Female; Hirsutism; Humans; Hyperandrogenism; Hyperplasia; Leptin; Leydig Cell Tumor; Metabolic Syndrome; Middle Aged; Obesity; Ovarian Neoplasms

Obesity is characterized by hyperinsulinemia, hyperleptinemia, and an increase in islet volume. While the mechanisms that hasten the onset of diabetes in obese individuals are not known, it is possible that the adipose-derived hormone leptin plays a role. In addition to its central actions, leptin exerts biological effects by acting in peripheral tissues including the endocrine pancreas. To explore the impact of disrupting leptin signaling in the pancreas on beta cell growth and/or function, we created pancreas-specific leptin receptor (ObR) KOs using mice expressing Cre recombinase under the control of the pancreatic and duodenal homeobox 1 (Pdx1) promoter. The KOs exhibited improved glucose tolerance due to enhanced early-phase insulin secretion, and a greater beta cell mass secondary to increased beta cell size and enhanced expression and phosphorylation of p70S6K. Similar effects on p70S6K were observed in MIN6 beta cells with knockdown of the ObR gene, suggesting crosstalk between leptin and insulin signaling pathways. Surprisingly, challenging the KOs with a high-fat diet led to attenuated acute insulin secretory response to glucose, poor compensatory islet growth, and glucose intolerance. Together, these data provide direct genetic evidence, from a unique mouse model lacking ObRs only in the pancreas, for a critical role for leptin signaling in islet biology and suggest that altered leptin action in islets is one factor that contributes to obesity-associated diabetes.

Topics: Animals; Body Weight; Cell Size; Diabetes Mellitus; Female; Glucose; Glucose Tolerance Test; Hyperplasia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Leptin; Male; Mice; Mice, Knockout; Obesity; Pancreas; Phosphorylation; Receptors, Leptin; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction

Recent evidence suggests that the adipose tissue-derived cytokine leptin (LEP) is involved in modulation of growth and differentiation of normal small intestine. The purpose of the present study was to evaluate the effects of parenteral LEP on structural intestinal adaptation, cell proliferation and apoptosis in a rat model of short bowel syndrome (SBS). Male Sprague-Dawley rats were divided into three experimental groups: Sham rats underwent bowel transection and re-anastomosis, SBS-rats underwent a 75% small bowel resection, and SBS-LEP-rats underwent bowel resection and were treated with LEP given subcutaneously at a dose of 20 mug/kg, once daily, from day 3 through 14. Parameters of intestinal adaptation (bowel and mucosal weights, mucosal DNA and protein, villus height and crypt depth in jejunum and ileum), enterocyte proliferation and enterocyte apoptosis were determined on day 15 following operation. Ileal tissue samples were taken for detection of bax and bcl-2 gene expression using RT-PCR technique. Statistical analysis was performed using the non-parametric Kruskal-Wallis ANOVA test, with P<0.05 considered statistically significant. Treatment with subcutaneous LEP resulted in a significant increase in jejunal (17%, P<0.05) and ileal (13%, P<0.05) bowel weight, jejunal (10%, P<0.05) and ileal (25%, P<0.05) mucosal weight, jejunal (26%, P<0.05) and ileal (38%, P<0.05) mucosal DNA, ileal (25%, P<0.05) mucosal protein, jejunal (41%, P<0.05) and ileal (21%, P<0.05) villus height, jejunal (37%, P<0.05) crypt depth, and jejunal (24%, P<0.05) and ileal (21%, P<0.05) enterocyte proliferation compared to SBS-animals. Enterocyte apoptosis increased significantly after bowel resection in jejunum and ileum compared to sham animals and was accompanied by an increased bax gene expression and a decreased bcl-2 gene expression in ileal samples. SBS-LEP rats showed a trend toward a decrease in enterocyte apoptosis in ileum and a mild decrease in bax gene expression compared to SBS-untreated animals. In conclusion, in a rat model of SBS parenteral LEP stimulates structural intestinal adaptation. Increased cell proliferation and decreased cell death via apoptosis may be responsible for this increased cell mass.

Topics: Adaptation, Physiological; Analysis of Variance; Animals; Apoptosis; Cell Proliferation; Enterocytes; Hyperplasia; Intestinal Mucosa; Leptin; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome; Statistics, Nonparametric

The aim of our investigation was the detection of endocrine-metabolic disorders in patients with hyperplastic processes of endomyometrium, uterine cervix and mammary glands. 88 patients of reproductive age with several gynaecological complaints have been investigated. 72 patients with hyperplastic processes in endomyometrium, uterine cervix (hyperplasia, polyposis, myoma) and mammary glands (fibroadenomatosis, adenomatosis) were selected in main group. Control group consisted of 16 patients without any hyperplastic processes of reproductive organs. Metabolic syndrome in main group was revealed in 28% of cases, in control - 18,8% (chi(2)=3,95, p=0,047); insulin resistance - 37,5% and 18,7% (chi(2)=4,59, p=0,033), respectively; obesity - 52,8% and 25,0% (chi(2)=4,05, p=0,045), respectively; dyslipidemia - 52,8% and 0,0%; hypertension - 26,4% and 12,5% (chi(2)=1,88, p=NS), respectively. Blood leptin level in main group was - 13,7+/-10,9 ng/ml, and in control - 5,0+/-2,9 ng/ml (p=0,005). Our results suggest that metabolic syndrome and its components significantly influences the formation of hyperplastic processes of endomyometrium, uterine cervix and mammary glands. Blood leptin level is significantly increased in patients with hyperplastic pathologies.

Topics: Adult; Breast Neoplasms; Cervix Uteri; Endocrine System Diseases; Female; Humans; Hyperplasia; Leptin; Mammary Glands, Human; Metabolic Syndrome; Reproduction; Uterine Cervical Neoplasms

Dietary supplementation with conjugated linoleic acids (CLA) has a fat-reducing effect in various species, but induces severe hyperinsulinaemia and hepatic steatosis in the mouse. This study aimed to determine the causes of the deleterious effects of CLA on insulin homeostasis.. The chronology of adipose and liver weight, hepatic triglyceride accumulation and selected blood parameters, including lipids, insulin, leptin and adiponectin, was determined in C57BL/6J female mice fed a 1% isomeric mixture of CLA for various periods of time ranging from 2 to 28 days. Insulin secretion was measured in 1-h static incubations of pancreatic islets, and pancreas morphometric parameters were determined in mice fed CLA for 28 days.. Plasma levels of leptin and adiponectin sharply decreased after 2 days of CLA feeding, although adipose tissue mass only decreased after day 6. Hyperinsulinaemia developed at day 6 and consistently worsened up to day 28, in parallel with increases in hepatic lipid content. Islets from CLA-fed mice displayed three- to four-fold increased rates of glucose-stimulated insulin secretion, both in the absence and presence of isobutyl methylxanthine or carbachol. The increased insulin-releasing capacity of islets from CLA-fed mice was explained by an increase in beta cell mass and number.. The data suggest that CLA supplementation induces a profound reduction of leptinaemia and adiponectinaemia, followed by hyperinsulinaemia due to the increased secretory capacity of pancreatic islets, leading, in turn, to liver steatosis. These observations cast doubt on the safety of dietary supplements containing CLA.

Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Disease Models, Animal; Female; Hyperinsulinism; Hyperplasia; Insulin; Insulin Secretion; Intercellular Signaling Peptides and Proteins; Islets of Langerhans; Leptin; Linoleic Acids, Conjugated; Liver; Mice; Mice, Inbred C57BL; Organ Size; Triglycerides

There is an increased incidence of renal glomerulosclerosis in obese individuals. One of the major structural changes observed in nephropathy is the increase in kidney size, which may occur due to hypertrophy or changes in the rate of hyperplasia or apoptosis. Here we investigated whether leptin, the product of the obese (ob) gene which is found at high plasma levels in obese and diabetic individuals, alters any of these parameters.. We show that leptin increased hypertrophy of these cells. This was indicated by an approximately 33% increase in cell size and 40% increase in leucine incorporation. Furthermore, we show that the hypertrophic effect of leptin was mediated via PI 3-kinase and ERK1/2 by using the inhibitors LY294002 and PD98059, respectively. We also confirm that leptin activates both PI 3-kinase and ERK1/2 in these cells. We show that hyperplasia was not affected by leptin by measuring rat glomerular mesangial cell number and by assessing bromodeoxyuridine uptake. Leptin also did not alter caspase 3-like activity under control conditions or upon induction of apoptosis by ultraviolet light, suggesting that apoptosis was not regulated by leptin in these cells.. Our results show that leptin induced glomerular mesangial cell hypertrophy via PI 3-kinase and ERK1/2, and that hyperplasia and apoptosis were not altered by leptin. The hypertrophic effect of leptin may play a role in the pathophysiology of nephropathy associated with obesity.

Topics: Animals; Apoptosis; Cell Size; Cells, Cultured; Chromones; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Glomerular Mesangium; Hyperplasia; Hypertrophy; Kidney; Leptin; Leucine; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Rats

Enlarged fat cells and leptin hypersecretion are hallmarks of common obesity.. The objective of this study was to investigate fat cell size and leptin production in the basal state after long-term steady-state weight reduction to the nonobese state.. This prospective case-control study had a duration of 3 +/- 1 (mean +/- sd) yr.. Twenty-five obese women (cases) were studied. Each case was compared with a control subject matched for age, sex, and body mass index (BMI) at nadir of weight for the cases.. This study was conducted at Karolinska University Hospital (Stockholm, Sweden).. The subjects were followed until they reached a steady-state weight reduction after lifestyle modification or bariatric surgery (cases). Treatment target was the nonobese state (BMI < 30 kg/m2). Subcutaneous adipose tissue secretion of leptin, serum leptin levels, and fat cell volume were determined after an overnight fast.. Ten obese women (40%) reached the nonobese state. This was accompanied by marked decreases in fat cell volume, leptin secretion, and serum leptin concentrations (P < 0.0001). The postobese cases had 43% smaller fat cell volume (P = 0.0008), 68% lower adipocyte leptin production (P = 0.001), and 54% lower serum leptin levels (P = 0.0007) than control subjects, despite almost identical percent body fat in the two groups. Fat cell volume, but not percent body fat or BMI, was directly proportional to leptin secretion and serum leptin concentrations.. Adipose tissue hyperplasia (too many small fat cells) and low leptin production resulting in relative hypoleptinemia in the fasting (basal) state are common features of the postobese state in women.

Topics: Adipocytes; Adipose Tissue; Adult; Body Mass Index; Case-Control Studies; Female; Humans; Hyperplasia; Leptin; Middle Aged; Obesity; Prospective Studies; Weight Loss

Human obesity is associated with elevated leptin levels and a high risk of death from cardiovascular disease. In the present study, we investigated the effects of leptin on vascular wound healing and arterial lesion growth in mice.. Wild-type mice placed on an atherogenic, high-fat diet had elevated (9-fold) leptin levels compared with their counterparts maintained on normal chow, and the former demonstrated significantly enhanced neointimal thickening after carotid artery injury with ferric chloride. The lesions forming in response to injury strongly expressed leptin receptor mRNA and protein. Unexpectedly, the atherogenic diet had no effect on injured vessels from leptin-deficient ob/ob mice despite aggravating obesity, diabetes, and hyperlipidemia in these animals. Daily administration of leptin to ob/ob mice during the 3-week period after injury reversed this phenotype, dramatically increasing neointimal thickness and the severity of luminal stenosis. Exogenous leptin also enhanced lesion growth and increased cellular proliferation in injured arteries from wild-type mice but had no effect on vessels from leptin receptor-deficient db/db mice.. Our results raise the possibility that there might be a direct, leptin receptor-mediated link between the hyperleptinemia in human obesity and the increased risk for cardiovascular complications associated with this condition.

Topics: Animals; Aorta; Arteriosclerosis; Carotid Arteries; Chlorides; Diet, Atherogenic; Dietary Fats; Disease Models, Animal; Ferric Compounds; Gene Expression Regulation; Hyperplasia; Leptin; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Obesity; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; RNA, Messenger; Tunica Intima

Obesity is a major risk factor for the development of heart failure. Importantly, it is now appreciated that a change in the number of myocytes is one of multiple structural and functional alterations (remodeling) leading to heart failure. Here we investigate the effect of leptin, the product of the obese (ob) gene, on proliferation of human and murine cardiomyocytes. Leptin caused a time- and dose-dependent significant increase in proliferation of HL-1 cells that was inhibited by preincubation with PD98059 and LY294002, suggesting that leptin mediated proliferation via extracellular signal-regulated kinase-1/2- and phosphatidylinositol-3-kinase-dependent signaling pathways. We confirmed that leptin activates both extracellular signal-regulated kinase-1/2 phosphorylation and association of phosphatidylinositol-3-kinase (regulatory p85 subunit) with phosphotyrosine immunoprecipitates. We also examined bromodeoxyuridine incorporation as a measure of new DNA synthesis and demonstrated a stimulatory effect of leptin in both HL-1 cells and human cardiomyocytes. Bromodeoxyuridine incorporation in HL-1 cells was inhibited by PD98059 and LY294002. Our results establish a mitogenic effect of leptin in cardiomyocytes and provide additional evidence for a potential direct link between leptin and cardiac remodeling in obesity.

Topics: Animals; Bromodeoxyuridine; Cell Line; Child, Preschool; Humans; Hyperplasia; Intracellular Membranes; Leptin; Mice; Mitogen-Activated Protein Kinases; Myocytes, Cardiac; Phosphatidylinositol 3-Kinases; Signal Transduction; Ventricular Remodeling

Neonatal treatment of rats with monosodium L-glutamate, which destroys hypothalamic arcuate nucleus neuronal bodies, induces several metabolic abnormalities; as a result, rats develop a phenotype of pseudoobesity. This study was designed to explore, in the monosodium L-glutamate-treated female rat, the influence of chronic hyperleptinemia on adrenal cortex functionality. For this purpose, we evaluated in control and hypothalamic-damaged rats: (a) in vivo and in vitro adrenocortical function, (b) adrenal leptin receptor immunodistribution and mRNA expression, and (c) whether the inhibitory effect of leptin on adrenal function remains. Our results indicate that, compared to normal counterparts, pseudoobese animals displayed (1) hyperadiposity, despite being hypophagic and of lower body weight, (2) in vivo and in vitro enhanced adrenocortical response to ACTH stimulation, (3) an in vitro adrenal fasciculata-reticularis cell hyper-sensitivity to ACTH stimulus, (4) hyperplasia of their adrenal zona fasciculata cells, and (5) adrenal fasciculata-reticularis cell refractoriness to the inhibitory effect of leptin on ACTH-stimulated glucocorticoid production due, at least in part, to decreased adrenal leptin receptor expression. These data further support that increased hypothalamo-pituitary-adrenal axis function, in the adult neurotoxin-lesioned female rat, is mainly dependent on the development of both hyperplasia of adrenal zona fasciculata and adrenal gland refractoriness to leptin inhibitory effect. Our study supports that adrenal leptin resistance could be responsible, at least in part, for enhanced glucocorticoid circulating levels in this phenotype of obesity.

Topics: Adrenal Cortex; Adrenal Glands; Adrenocorticotropic Hormone; Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Drug Resistance; Female; Glucocorticoids; Hyperplasia; Hypothalamic Diseases; Leptin; Obesity; Rats; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Sodium Glutamate; Zona Fasciculata

The physiological importance of and therapeutic interest in dehydroepiandrosterone (DHEA) has been predominantly in relation to its action as an inhibitor of the promotion and progression of several kinds of tumours, including those of breast, prostate, lung, colon, liver and skin tissues. The aim of the present study was to determine the role of DHEA in diethylstilboestrol (DES)-induced pituitary hyperplasia. Female Sprague-Dawley rats were divided into four treatment groups: DES (implanted s.c. with a 20 mg DES pellet), DHEA (two 50 mg DHEA pellets), DHEA/DES (both DHEA and DES pellets), and controls (not implanted). Every week, all rats were weighed and cycled, and jugular blood samples were obtained. After 7 weeks, rats were killed. Hypophyses were removed and weighed, and serum prolactin, GH, IGF-I and leptin levels were assayed by RIA. DHEA cotreatment reduced pituitary enlargement by 39% in DES-treated rats. It also reduced the hyperprolactinaemia (280.4+/-43.6 ng/ml for DHEA/DES vs 823.5+/- 127.1 ng/ml for DES) and partially reversed the loss of body weight induced by DES. DHEA treatment did not modify the effects of DES on serum GH, IGF-I and leptin levels. But DHEA per se also increased pituitary weight and induced hyperprolactinaemia, although to a lesser degree than DES. We conclude that DHEA administration has beneficial effects on oestrogen-induced pituitary hyperplasia and hyperprolactinaemia, but the fact that DHEA per se also induces diverse hormonal effects and a slight pituitary enlargement limits its use as a possible therapeutic drug.

Topics: Animals; Dehydroepiandrosterone; Diethylstilbestrol; Female; Growth Hormone; Hyperplasia; Insulin-Like Growth Factor I; Leptin; Models, Animal; Organ Size; Pituitary Gland; Prolactin; Rats; Rats, Sprague-Dawley

Morbid obesity is the result of massive expansion of white adipose tissue (WAT) and requires recruitment of adipocyte precursor cells and their supporting infrastructure. To characterize the change in the expression profile of the preexisting WAT at the start of obesity, when adipocyte hypertrophy is present but hyperplasia is still minimal, we employed a cDNA subtraction screen for genes differentially expressed in epididymal fat pads harvested 1 wk after the start of a 60% fat diet. Ninety-six genes were upregulated by at least 50% above the WAT of control rats receiving a 4% fat diet. Of these genes, 30 had not previously been identified. Sixteen of the 96 genes, including leptin, adipocyte complement-related protein 30 kDa, and resistin, were predicted to encode a signal peptide. Ten of the 16 had been previously identified in other tissues and implicated in cell growth, proliferation, differentiation, cell cycle control, and angiogenesis. One was a novel gene. Twenty-nine novel fragments were identified. Thus, at the onset of high-fat-diet-induced obesity in rats, adipose tissue increases its expression of factors previously implicated in the expansion of nonadipocyte tissues and of several uncharacterized novel factors. The only one of these thus far characterized functionally was found to promote lipogenesis.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Blood Proteins; Cytoskeletal Proteins; Dietary Fats; Gene Expression Profiling; Hormones, Ectopic; Hyperplasia; Hypertrophy; Intercellular Signaling Peptides and Proteins; Leptin; Lipids; Male; Mitochondria; Nerve Growth Factor; Nutritional Physiological Phenomena; Obesity; Oxygen Consumption; Proteins; Rats; Rats, Sprague-Dawley; Resistin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transcription Factors; Tumor Necrosis Factor-alpha

To investigate the relationships of fat cell weight (FCW) as well as of estimated total adipose cell number to fasting plasma leptin concentration.. Cross-sectional correlational study.. A sample of 63 men (mean age+/-s.d.: 36+/-4 y) and 42 premenopausal women (35+/-5 y).. Adipose tissue (AT) biopsies were obtained in order to determine FCW as well as estimated adipose cell number. Fasting plasma leptin and insulin concentrations as well as various fatness and body fat distribution variables (underwater weighing and computed tomography) were also measured.. In both genders, mean FCW as well as the estimated adipose cell number were significantly correlated with body fatness and AT distribution variables (0.41

Topics: Adipocytes; Adipose Tissue; Adult; Biopsy; Body Composition; Cell Count; Cell Size; Cross-Sectional Studies; Fasting; Female; Humans; Hyperplasia; Hypertrophy; Insulin; Leptin; Male; Regression Analysis

Stimulation ofcortisol secretion by food intake has been implicated in the pathogenesis of some cases of ACTH-independent Cushing's syndrome, via an aberrant response of the adrenal glands to gastric inhibitory polypeptide (GIP). We report here a novel case of food-dependent Cushing's syndrome in a patient with bilateral macronodular adrenal hyperplasia. In this patient we were able to confirm a paradoxical stimulation of cortisol secretion by GIP in vivo as well as in vitro on dispersed tumor adrenal cells obtained at surgery. In addition to GIP, in vitro stimulation of these cultured tumor adrenal cells with leptin, the secreted product of the adipocyte, induced cortisol secretion. By comparison, no such stimulation was observed in vitro in adrenal cells obtained from another patient with bilateral macronodular adrenal hyperplasia and Cushing's syndrome that did not depend on food intake, in tumor cells obtained from a solitary cortisol-secreting adrenal adenoma, and in normal human adrenocortical cells. These results demonstrate that as in previously described cases of food-dependent Cushing's syndrome, GIP stimulated cortisol secretion from the adrenals of the patient reported here. Therefore, they indicate that such a paradoxical response probably represents the hallmark of this rare condition. In addition, they suggest that leptin, which normally inhibits stimulated cortisol secretion in humans, participated in cortisol hypersecretion in this case. Further studies in other cases of food-dependent Cushing's syndrome, however, will be necessary to better ascertain the pathophysiological significance of this finding.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Female; Food; Gastric Inhibitory Polypeptide; Humans; Hydrocortisone; Hyperplasia; Leptin; Middle Aged