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

Abstract

Transgenic mice designated αMUPA 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, αMUPA mice spontaneously consumed less food (≃20%), exhibited reduced body weight (≃20%) and length (≃6%), and also prolonged life span (≃20%). The αMUPA phenotype is thus reminiscent of experimental animals in which dietary restriction enhances longevity. Reduced eating and body weight were observed in αMUPA mice shortly after weaning, and these levels were maintained virtually throughout their lifetime. αMUPA mice also exhibited lower levels of blood sugar (≃9%), smaller litter size (≃14%), and lower birth frequency (≃10%). In the adult αMUPA 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 αMUPA 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 αMUPA experimental model may have implications for normal mice.