Transgenic mice overexpressing urokinase-type plasminogen activator in the brain exhibit reduced food consumption, body weight and size, and increased longevity

Transgenic mice designated alpha MUPA overproduce in many brain sites the urokinase-type plasminogen activator (uPA), a protease implicated in fibrinolysis and extracellular proteolysis. Here we report that, compared to their parental wild-type control, alpha MUPA mice spontaneously consumed less food (approximate to 20%), exhibited reduced body weight (approximate to 20%) and length (approximate to 6%), and also prolonged life span (approximate to 20%). The alpha MUPA phenotype is thus reminiscent of experimental animals in which dietary restriction enhances longevity. Reduced eating and body weight were observed in alpha MUPA mice shortly after weaning, and these levels were maintained virtually throughout their lifetime. alpha MUPA mice also exhibited lower levels of blood sugar (approximate to 9%), smaller litter size (approximate to 14%), and lower birth frequency (approximate to 10%). In the adult alpha MUPA brain, uPA mRNA has been localized through in situ hybridization also in neuronal cells of the hypothalamic paraventricular nucleus, a region implicated in feeding behavior. No signals of uPA mRNA could be detected in the paraventricular nucleus of control mice. It is suggested that in alpha MUPA mice, overproduction of uPA in brain sites controlling feeding leads to reduced food consumption that, in turn, results in retardation of growth and body weight and also in increased longevity. The alpha MUPA experimental model may have implications for normal mice.