title: Leptin administered in physiological or pharmacological doses does not regulate circulating angiogenesis factors in humans.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00140205 and NCT00130117.
  
  
  BACKGROUND
  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.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: K N
authors.initials: KN
authors.lastname: Aronis
authors.forename: K N
authors.initials: KN
authors.lastname: Diakopoulos
authors.forename: C G
authors.initials: CG
authors.lastname: Fiorenza
authors.forename: J P
authors.initials: JP
authors.lastname: Chamberland
authors.forename: C S
authors.initials: CS
authors.lastname: Mantzoros
mesh_terms: D000293:Adolescent; D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000097:blood*; D042683:Angiopoietin-1 / Q000097:blood; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000097:blood; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D020738:Leptin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000097:blood; D013851:Thinness / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D055815:Young Adult
chemical_list: D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D016228:Endothelial Growth Factors; D020738:Leptin; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; C075278:platelet-derived growth factor A; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; C415771:metreleptin