title: New function for an old enzyme: NEP deficient mice develop late-onset obesity.
abstract: BACKGROUND
  According to the World Health Organization (WHO) there is a pandemic of obesity with approximately 300 million people being obese. Typically, human obesity has a polygenetic causation. Neutral endopeptidase (NEP), also known as neprilysin, is considered to be one of the key enzymes in the metabolism of many active peptide hormones.
  
  
  RESULTS
  An incidental observation in NEP-deficient mice was a late-onset excessive gain in body weight exclusively from a ubiquitous accumulation of fat tissue. In accord with polygenetic human obesity, mice were characterized by deregulation of lipid metabolism, higher blood glucose levels, with impaired glucose tolerance. The key role of NEP in determining body mass was confirmed by the use of the NEP inhibitor candoxatril in wild-type mice that increased body weight due to increased food intake. This is a peripheral and not a central NEP action on the switch for appetite control, since candoxatril cannot cross the blood-brain barrier. Furthermore, we demonstrated that inhibition of NEP in mice with cachexia delayed rapid body weight loss. Thus, lack in NEP activity, genetically or pharmacologically, leads to a gain in body fat.
  
  
  CONCLUSIONS
  In the present study, we have identified NEP to be a crucial player in the development of obesity. NEP-deficient mice start to become obese under a normocaloric diet in an age of 6-7 months and thus are an ideal model for the typical human late-onset obesity. Therefore, the described obesity model is an ideal tool for research on development, molecular mechanisms, diagnosis, and therapy of the pandemic obesity.
authors.affiliation: Department for Biochemical Neurobiology, Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Becker
authors.forename: Wolf-Eberhard
authors.initials: WE
authors.lastname: Siems
authors.forename: Reinhart
authors.initials: R
authors.lastname: Kluge
authors.forename: Florian
authors.initials: F
authors.lastname: Gembardt
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Michael
authors.initials: M
authors.lastname: Schirner
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D017668:Age of Onset; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D015260:Neprilysin / Q000172:deficiency* / Q000235:genetics*; D009765:Obesity / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain
chemical_list: D001786:Blood Glucose; D015260:Neprilysin