New function for an old enzyme: NEP deficient mice develop late-onset obesity.
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.
Becker
Matthias
M
Department for Biochemical Neurobiology, Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
Siems
Wolf-Eberhard
WE
Kluge
Reinhart
R
Gembardt
Florian
F
Schultheiss
Heinz-Peter
HP
Schirner
Michael
M
Walther
Thomas
T
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
D001786:Blood Glucose; D015260:Neprilysin