Wa. Banks et al., Obesity-inducing lesions of the central nervous system alter leptin uptakeby the blood-brain barrier, LIFE SCI, 69(23), 2001, pp. 2765-2773
Leptin regulates body adiposity by decreasing feeding and increasing thermo
genesis. Obese humans and some obese rodents are resistant to peripherally
administered leptin, suggesting a defect in the transport of leptin across
the blood-brain barrier (BBB). Defective transport of exogenous leptin occu
rs in some models of obesity, but in other models transport is normal. This
shows that factors other than obesity are associated with impairment of le
ptin transport across the BBB. In order to further investigate these factor
s, we determined leptin transport in rats made obese by lesioning of the ve
ntromedial hypothalamus (VMH), paraventricular nucleus (PVN), or posterodor
sal amygdala (PDA). These regions all contain leptin receptors and lesions
there induce obesity and hyperleptinemia and alter the levels of many feedi
ng hormones which might participate in leptin transporter regulation. We me
asured the uptake of radioactively labeled leptin by the BBB by multiple-ti
me regression analysis which divides uptake into a reversible phase (Vi, e.
g., receptor/transporter binding to the brain endothelial cell) and an irre
versible phase (Ki, complete transport across the BBB). Leptin uptake was n
ot affected in rats with VMH lesions. No significant change occurred in the
entry rate (Ki) for any group, although Ki declined by over 35% in rats wi
th PVN lesions. Decreased uptake was observed in rats with PVN lesions and
with PDA lesions. This was primarily due to a reduced Vi (about 21% for the
PDA). This decreased uptake is most likely explained by decreased binding
of leptin to the brain endothelial cell, which could be because of decrease
d binding by either receptors or transporters. This suggests that some of t
he feeding hormones controlled by the PVN and PDA may participate in regula
ting leptin uptake by the BBB. (C) 2001 Elsevier Science Inc. All rights re
served.