Effects of lipopolysaccharide on leptin transport across the blood-brain barrier

Leptin is a 16-kDa protein secreted by fat cells and transported into the brain where it decreases appetite and increases body temperature. Leptin transport is saturable and regulated by epinephrine, triglycerides, and starvation. Lipopolysaccharide (LPS) is derived from bacterial cell walls and also decreases appetite and increases body temperature. LPS is known to increase leptin levels in serum and to affect the passage of other regulatory proteins across the blood-brain barrier (BBB). Here, we examined the ability of LPS, at doses which induce weight loss, to modify the BBB transport of radioactive leptin (I-Lep). The transport rate of intravenously injected I-Lep was decreased by 50-60% from 8 to 12 h after a single i.p. injection of LPS (3 mg/kg). The effect of LPS was dose-dependent. In comparison to the brain/serum ratio, the baseline cerebrospinal fluid (CSF)/serum ratio for I-Lep was much lower and not inhibited by LPS. LPS did not affect I-Lep transport when studied by the brain perfusion method nor was Ob-Ra mRNA expression in isolated brain microvessels altered, demonstrating that a circulating factor rather than altered BBB function was responsible for inhibition. Brain perfusion showed that LPS was not this factor. Serum leptin was doubled and serum triglycerides increased by 44% after LPS administration, suggesting these to be the circulating inhibitory factors. In conclusion, a single dose of LPS has long-lasting effects on the transport of serum leptin across the BBB that are likely mediated through self-inhibition and triglycerides.