title: Effects of cell-type specific leptin receptor mutation on leptin transport across the BBB.
abstract: The functions of leptin receptors (LRs) are cell-type specific. At the blood-brain barrier, LRs mediate leptin transport that is essential for its CNS actions, and both endothelial and astrocytic LRs may be involved. To test this, we generated endothelia specific LR knockout (ELKO) and astrocyte specific LR knockout (ALKO) mice. ELKO mice were derived from a cross of Tie2-cre recombinase mice with LR-floxed mice, whereas ALKO mice were generated by a cross of GFAP-cre with LR-floxed mice, yielding mutant transmembrane LRs without signaling functions in endothelial cells and astrocytes, respectively. The ELKO mutation did not affect leptin half-life in blood or apparent influx rate to the brain and spinal cord, though there was an increase of brain parenchymal uptake of leptin after in situ brain perfusion. Similarly, the ALKO mutation did not affect blood-brain barrier permeation of leptin or its degradation in blood and brain. The results support our observation from cellular studies that membrane-bound truncated LRs are fully efficient in transporting leptin, and that basal levels of astrocytic LRs do not affect leptin transport across the endothelial monolayer. Nonetheless, the absence of leptin signaling at the BBB appears to enhance the availability of leptin to CNS parenchyma. The ELKO and ALKO mice provide new models to determine the dynamic regulation of leptin transport in metabolic and inflammatory disorders where cellular distribution of LRs is shifted.
authors: Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
authors: Hung
authors: H
authors: Hsuchou
authors: Abba J
authors: AJ
authors: Kastin
authors: Hong
authors: H
authors: Tu
authors: Emily N
authors: EN
authors: Markadakis
authors: Kirsten P
authors: KP
authors: Stone
authors: Yuping
authors: Y
authors: Wang
authors: Steven B
authors: SB
authors: Heymsfield
authors: Streamson S
authors: SS
authors: Chua
authors: Silvana
authors: S
authors: Obici
authors: I Jack
authors: IJ
authors: Magrisso
authors: Weihong
authors: W
authors: Pan
references: Diabetes. 2004 May;53(5):1253-60
references: 15111494
references: Curr Pharm Des. 2008;14(16):1615-9
references: 18673203
references: Am J Physiol Endocrinol Metab. 2005 Sep;289(3):E403-11
references: 15870101
references: Peptides. 1996;17(2):305-11
references: 8801538
references: J Neurochem. 1998 Oct;71(4):1761-4
references: 9751212
references: Brain Res. 2000 Aug 4;873(1):165-7
references: 10915826
references: Mamm Genome. 2004 Sep;15(9):677-85
references: 15389315
references: Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E10-5
references: 12618361
references: EMBO J. 2006 Mar 8;25(5):932-42
references: 16482222
references: Peptides. 2001 Dec;22(12):2127-36
references: 11786200
references: J Neurochem. 2010 Dec;115(5):1288-98
references: 20977476
references: Genesis. 2007 May;45(5):292-9
references: 17457931
references: Nat Neurosci. 2007 Nov;10(11):1369-76
references: 17965657
references: Neurochem Res. 2008 Oct;33(10):2035-43
references: 18373195
references: Brain. 2009 Apr;132(Pt 4):889-902
references: 19293246
references: Peptides. 2010 Apr;31(4):757-76
references: 20093161
references: FASEB J. 2010 Jul;24(7):2281-91
references: 20223942
references: Endocrinology. 2002 Mar;143(3):775-83
references: 11861497
references: Peptides. 2006 Jun;27(6):1420-5
references: 16293343
references: J Anat. 2002 Jun;200(6):629-38
references: 12162730
references: J Cell Physiol. 2008 Feb;214(2):301-5
references: 17620316
references: J Cell Physiol. 2007 Jul;212(1):215-22
references: 17323382
references: Endocrinology. 2006 May;147(5):2086-7
references: 16617152
references: J Mol Neurosci. 2011 Mar;43(3):478-84
references: 21086065
references: Rev Neurosci. 1993 Oct-Dec;4(4):365-72
references: 8275277
references: Peptides. 2009 Dec;30(12):2275-80
references: 19747514
references: Exp Neurol. 2006 Mar;198(1):222-33
references: 16412421
references: Transgenic Res. 2008 Oct;17(5):919-28
references: 18483774
references: Brain Res. 2002 Sep 20;950(1-2):130-6
references: 12231237
references: J Biol Chem. 2008 Jun 27;283(26):18238-47
references: 18367451
references: Diabetes. 1999 Feb;48(2):279-86
references: 10334302
references: Exp Neurol. 2007 Jan;203(1):116-22
references: 16973162
references: Peptides. 1999 Dec;20(12):1449-53
references: 10698121
references: Endocrinology. 2008 Mar;149(3):877-85
references: 18039787
references: Endocrinology. 1998 Aug;139(8):3485-91
references: 9681499
references: Life Sci. 2001 May 4;68(24):2705-14
references: 11400913
references: Endocrinology. 2000 Jun;141(6):1955-61
references: 10830277
references: Endocrinology. 2008 Jun;149(6):2798-806
references: 18292187
references: Neuroendocrinology. 2000 Sep;72(3):171-8
references: 11025411