title: Alterations of leptin in the course of inflammation and severe sepsis.
abstract: BACKGROUND
  The adipokine leptin regulates energy expenditure, vascular function, bone and cartilage growth as well as the immune system and systemic inflammatory response. Several activating effects towards T cells, monocytes, endothelium cells and cytokine production have been reported suggesting a protective role of leptin in the setting of an acute systemic inflammation. However, the pathophysiological role of leptin during severe sepsis is currently not elucidated in detail. This study aims to investigate leptin expression in cultured human adipocytes within an inflammatory model and in patients suffering from severe sepsis and evaluates treatment effects of drotrecogin alpha (activated) (DAA), the recombinant form of human activated protein C.
  
  
  METHODS
  In an in-vitro inflammatory model of adipocyte cell-culture the effect of DAA on leptin mRNA expression was evaluated. Synthesis of mRNA was measured by quantitative polymerase chain reaction (qPCR). Additionally, supernatants of these adipocytes as well as serum levels of adiponectin were measured in blood of 104 severe septic patients by ELISA-method. 26 patients were treated with DAA (DAA+), 78 patients were not treated with DAA (DAA-).
  
  
  RESULTS
  Stimulation of human adipocytes with TNF alpha over 6 and 24 hours resulted in a significant decrease by 46% and 59% of leptin mRNA transcripts compared to un-stimulated controls (p < 0.05). Leptin levels of supernatants of adipocyte culture decreased by 25% and 23% (p < 0.05) after incubation with TNF alpha after 6 and 24 hours. Incubation with DAA at 50 ng/ml DAA and 5 μg/ml doubled mRNA expression significantly at 24 hours (p < 0.05) but not at 6 hours. From day 1 to day 3 of sepsis, leptin levels increased in DAA+ compared to DAA- patients (p<0.10).
  
  
  CONCLUSIONS
  Leptin appears to be involved in the pathogenesis of a systemic inflammatory response during sepsis. Administration of DAA significantly increased leptin expression. The specific mechanism or even benefit of DAA towards leptin needs further ongoing research.
authors.affiliation: First Department of Medicine, University Medical Centre Mannheim (UMM), Faculty of Medicine Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Behnes
authors.forename: Martina
authors.initials: M
authors.lastname: Brueckmann
authors.forename: Siegfried
authors.initials: S
authors.lastname: Lang
authors.forename: Christian
authors.initials: C
authors.lastname: Putensen
authors.forename: Joachim
authors.initials: J
authors.lastname: Saur
authors.forename: Martin
authors.initials: M
authors.lastname: Borggrefe
authors.forename: Ursula
authors.initials: U
authors.lastname: Hoffmann
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D020738:Leptin / Q000096:biosynthesis / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000008:administration & dosage; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000008:administration & dosage; D018805:Sepsis / Q000188:drug therapy / Q000503:physiopathology*; D044967:Serum / Q000737:chemistry; D014158:Transcription, Genetic; D016896:Treatment Outcome
chemical_list: D020738:Leptin; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated