leptin and angiogenin

Leptin has been shown to regulate angiogenesis in animal and in vitro studies by upregulating the production of several pro-angiogenic factors, but its role in regulating angiogenesis has never been studied in humans.. The potential angiogenic effect of two doses of metreleptin (50 and 100 ng/ml) was evaluated in vitro, using a novel three-dimensional angiogenesis assay. Fifteen healthy, normoleptinaemic volunteers were administered both a physiological (0.1 mg/kg) and a pharmacological (0.3 mg/kg) single dose of metreleptin, in vivo, on two different inpatient admissions separated by 1-12 weeks. Serum was collected at 0, 6, 12 and 24 h after metreleptin administration. Twenty lean women, with leptin levels <5 ng/ml, were randomised in a 1:1 fashion to receive either physiological replacement doses of metreleptin (0.04-0.12 mg/kg q.d.) or placebo for 32 weeks. Serum was collected at 0, 8, 20 and 32 weeks after randomisation. Proteomic angiogenesis array analysis was performed to screen for angiogenic factors. Circulating concentrations of angiogenin, angiopoietin-1, platelet derived endothelial factor (PDGF)-AA, matrix metalloproteinase (MMP) 8 and 9, endothelial growth factor (EGF) and vascular EGF (VEGF) were also measured.. Both metreleptin doses failed to induce angiogenesis in the in vitro model. Although leptin levels increased significantly in response to both short-term and long-term metreleptin administration, circulating concentrations of angiogenesis markers did not change significantly in vivo.. This is the first study that examines the effect of metreleptin administration in angiogenesis in humans. Metreleptin administration does not regulate circulating angiogenesis related factors in humans.. ClinicalTrials.gov NCT00140205 and NCT00130117.. This study was supported by National Institutes of Health-National Center for Research Resources grant M01-RR-01032 (Harvard Clinical and Translational Science Center) and grant number UL1 RR025758. Funding was also received from the National Institute of Diabetes and Digestive and Kidney Diseases grants 58785, 79929 and 81913, and AG032030.

Topics: Adolescent; Adult; Angiogenesis Inducing Agents; Angiopoietin-1; Dose-Response Relationship, Drug; Endothelial Growth Factors; Female; Humans; Injections, Subcutaneous; Leptin; Male; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Neovascularization, Physiologic; Platelet-Derived Growth Factor; Ribonuclease, Pancreatic; Thinness; Vascular Endothelial Growth Factor A; Young Adult

Sixteen plasma markers of inflammation and oxidative stress were measured during OGTT in 54 subjects. Leptin, RBP4, CRP, OPN, ANG, MDC, and MCSF concentrations significantly decreased during OGTT (P<0.05). IL6, IL8, and MCP3 concentrations significantly increased during OGTT (P<0.05). These results provide evidence that glucose ingestion affects systemic inflammation and oxidative stress.

Topics: Aged; Biomarkers; Blood Glucose; C-Reactive Protein; Chemokine CCL2; Chemokine CCL22; Diabetes Mellitus; Female; Glucose; Glucose Tolerance Test; Humans; Inflammation; Interleukin-6; Leptin; Male; Middle Aged; Osteopontin; Oxidative Stress; Retinol-Binding Proteins, Plasma; Ribonuclease, Pancreatic

Adipose tissue produces both vascular growth factors and inhibitors. Since obesity is associated with expansion of the capillary bed in regional adipose depots the balance between these factors may favor angiogenesis.. To investigate the relationship between body mass index and serum concentrations of vascular growth factors in human subjects.. Vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D, soluble VEGF receptor-2 (sVEGFr2), hepatocyte growth factor (HGF), angiopoietin-2, angiogenin and endostatin concentrations were measured in serum collected from 58 lean (24 males, 34 female, mean BMI, 22.2+/-0.3) and 42 overweight and obese (16 males and 26 females, mean BMI, 33.5+/-1.2) subjects after an overnight fast.. Sexual dimorphism was apparent in the serum concentrations of VEGF-C, VEFG-D and angiopoietin-2 with significantly higher levels in female compared to male subject. VEGF, VEGF-C, VEGF-D, soluble VEGF receptor-2, angiopoietin-2, angiogenin and endostatin but not HGF were significantly elevated in overweight and obese subjects. Positive correlations between BMI and the serum concentrations of VEGF-C, VEGF-D, sVEGF-R2, angiopoietin-2, angiogenin and endostatin were observed even after adjustment for gender and age.. Increased levels of vascular growth factors as well as the angiogenesis inhibitor endostatin are present in overweight and obese subjects and may contribute to previously documented increased risk of metastatic disease in obese subjects with cancer.

Topics: Adiponectin; Adult; Analysis of Variance; Angiogenic Proteins; Angiopoietin-2; Endostatins; Female; Hepatocyte Growth Factor; Humans; Insulin Resistance; Leptin; Linear Models; Male; Middle Aged; Obesity; Overweight; Ribonuclease, Pancreatic; Sex Characteristics; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-2

Angiogenesis is regulated by a wide range of soluble mediators that are released locally or by distant organs that affect local angiogenesis through variations in systemic levels. Serum levels of angioregulatory mediators are important for muscle angiogenesis in response to physical activity; in addition, angioregulation is involved in disease development, and determination of systemic levels may therefore be useful in future clinical practice. The aim of the present study was to investigate whether physical activity alters systemic levels of angioregulatory mediators in healthy individuals.. The effects of physical activity on serum levels of pro- (angiogenin, basic fibroblast growth factor (bFGF), leptin) and antiangiogenic (endostatin) mediators were investigated. The levels were determined immediately before and after activity for healthy young athletes (all males, age 18 years) and elderly individuals (9 M, 11 F, age 68-88 years).. Elderly individuals showed higher pre-activity levels than the athletes for all mediators. The young athletes showed increased angiogenin and endostatin levels and decreased bFGF levels after 45 min of intensive physical activity, whereas leptin levels were not altered. Elderly individuals showed a similar decrease in bFGF levels after a 3-h mountain walk, but angiogenin, endostatin and leptin levels were not altered.. Serum levels of angioregulatory mediators depend on age, and standardization of physical activity prior to sampling will probably be necessary when evaluating the possible clinical use of these parameters.

Topics: Adolescent; Aged; Aged, 80 and over; Aging; Angiogenic Proteins; Endostatins; Female; Fibroblast Growth Factor 2; Humans; Leptin; Male; Motor Activity; Ribonuclease, Pancreatic; Running; Walking