Endothelial cell leptin receptor mutant mice have hyperleptinemia and reduced tissue uptake.
Hyperleptinemia is usually associated with obesity and leptin resistance. Endothelial cell leptin receptor knockout (ELKO) mice without a signaling membrane-bound leptin receptor in endothelia, however, have profound hyperleptinemia without signs of leptin resistance. Leptin mRNA in adipose tissue was unchanged. To test the hypothesis that the ELKO mutation results in delayed degradation and slowed excretion, we determined the kinetics of leptin transfer in groups of ELKO and wildtype mice after intravenous bolus injection of (125) I-leptin and the reference substance (131) I-albumin. The degradation pattern of (125) I-leptin in serum and brain homogenates at different time points between 10 and 60 min was measured by HPLC and acid precipitation. Although ELKO mice had reduced uptake of (125) I-leptin uptake by the brain and several peripheral organs, leptin was more stable in blood and tissue. There was no change in the rate of renal excretion. ELISA showed that serum soluble leptin receptor, known to antagonize leptin transport, had a 400-fold increase, probably contributing to the hyperleptinemia and reduced tissue uptake. Thus, the ELKO mutation unexpectedly increased the stability of leptin but suppressed its tissue uptake. These changes probably contribute to the known partial resistance of the ELKO mice to diet-induced obesity.
Blood-Brain Barrier Group, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA
Hung
H
Hsuchou
Bhavaani
B
Jayaram
Abba J
AJ
Kastin
Yuping
Y
Wang
Suidong
S
Ouyang
Weihong
W
Pan
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D001921:Brain / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D020738:Leptin / Q000097:blood* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D055550:Protein Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D014018:Tissue Distribution
D020738:Leptin; D012333:RNA, Messenger; D054411:Receptors, Leptin; D012709:Serum Albumin; C515447:leptin receptor, mouse