Effects of cell-type specific leptin receptor mutation on leptin transport across the BBB

Hung Hsuchou, Abba J. Kastin, Hong Tu, Emily N. Markadakis, Kirsten P. Stone, Yuping Wang, Steven B. Heymsfield, Streamson C. Chua, Jr., Silvana Obici, I. Jack Magrisso, Weihong Pan

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1392-1399
Number of pages8
JournalPeptides
Volume32
Issue number7
DOIs
StatePublished - Jul 2011

Fingerprint

Leptin Receptors
Leptin
Mutation
Astrocytes
Knockout Mice
Endothelium
Brain
Blood-Brain Barrier
Blood
Endothelial cells
Permeation
Half-Life
Monolayers
Spinal Cord
Endothelial Cells
Perfusion
Observation
Availability
Membranes
Degradation

Keywords

  • Astrocytes
  • BBB
  • CNS effects
  • Endothelial cells
  • Leptin
  • Transport

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Physiology
  • Cellular and Molecular Neuroscience

Cite this

Hsuchou, H., Kastin, A. J., Tu, H., Markadakis, E. N., Stone, K. P., Wang, Y., ... Pan, W. (2011). Effects of cell-type specific leptin receptor mutation on leptin transport across the BBB. Peptides, 32(7), 1392-1399. https://doi.org/10.1016/j.peptides.2011.05.011

Effects of cell-type specific leptin receptor mutation on leptin transport across the BBB. / Hsuchou, Hung; Kastin, Abba J.; Tu, Hong; Markadakis, Emily N.; Stone, Kirsten P.; Wang, Yuping; Heymsfield, Steven B.; Chua, Jr., Streamson C.; Obici, Silvana; Magrisso, I. Jack; Pan, Weihong.

In: Peptides, Vol. 32, No. 7, 07.2011, p. 1392-1399.

Research output: Contribution to journalArticle

Hsuchou, H, Kastin, AJ, Tu, H, Markadakis, EN, Stone, KP, Wang, Y, Heymsfield, SB, Chua, Jr., SC, Obici, S, Magrisso, IJ & Pan, W 2011, 'Effects of cell-type specific leptin receptor mutation on leptin transport across the BBB', Peptides, vol. 32, no. 7, pp. 1392-1399. https://doi.org/10.1016/j.peptides.2011.05.011
Hsuchou H, Kastin AJ, Tu H, Markadakis EN, Stone KP, Wang Y et al. Effects of cell-type specific leptin receptor mutation on leptin transport across the BBB. Peptides. 2011 Jul;32(7):1392-1399. https://doi.org/10.1016/j.peptides.2011.05.011
Hsuchou, Hung ; Kastin, Abba J. ; Tu, Hong ; Markadakis, Emily N. ; Stone, Kirsten P. ; Wang, Yuping ; Heymsfield, Steven B. ; Chua, Jr., Streamson C. ; Obici, Silvana ; Magrisso, I. Jack ; Pan, Weihong. / Effects of cell-type specific leptin receptor mutation on leptin transport across the BBB. In: Peptides. 2011 ; Vol. 32, No. 7. pp. 1392-1399.
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