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Harrison, L. ; Schriever, S.C. ; Feuchtinger, A. ; Kyriakou, E. ; Baumann, P. ; Pfuhlmann, K. ; Messias, A.C. ; Walch, A.K. ; Tschöp, M.H. ; Pfluger, P.T.

Fluorescent blood-brain barrier tracing shows intact leptin transport in obese mice.

Int. J. Obes. 43, 1305-1318 (2019)
Publ. Version/Full Text Postprint DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Background/objectives Individuals carrying loss-of-function gene mutations for the adipocyte hormone leptin are morbidly obese, but respond favorably to replacement therapy. Recombinant leptin is however largely ineffective for the vast majority of obese individuals due to leptin resistance. One theory underlying leptin resistance is impaired leptin transport across the blood-brain-barrier (BBB). Here, we aim to gain new insights into the mechanisms of leptin BBB transport, and its role in leptin resistance.Methods We developed a novel tool for visualizing leptin transport using infrared fluorescently labeled leptin, combined with tissue clearing and light-sheet fluorescence microscopy. We corroborated these data using western blotting.Results Using 3D whole brain imaging, we display comparable leptin accumulation in circumventricular organs of lean and obese mice, predominantly in the choroid plexus (CP). Protein quantification revealed comparable leptin levels in micro-dissected mediobasal hypothalami (MBH) of lean and obese mice (p = 0.99). We further found increased leptin receptor expression in the CP (p = 0.025, p = 0.0002) and a trend toward elevated leptin protein levels in the MBH (p = 0.17, p = 0.078) of obese mice undergoing weight loss interventions by calorie restriction or exendin-4 treatment.Conclusions Overall, our findings suggest a crucial role for the CP in controlling the transport of leptin into the cerebrospinal fluid and from there to target areas such as the MBH, potentially mediated via the leptin receptor. Similar leptin levels in circumventricular organs and the MBH of lean and obese mice further suggest intact leptin BBB transport in leptin resistant mice.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Choroid-plexus; Resistance; Receptor; Protein; Identification; Maintenance; Expression; Weight; Organs
Language english
Publication Year 2019
Prepublished in Year 2018
HGF-reported in Year 2018
ISSN (print) / ISBN 0307-0565
e-ISSN 1476-5497
Journal International Journal of Obesity
Quellenangaben Volume: 43, Issue: 6, Pages: 1305-1318 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Macmillan Building, 4 Crinan St, London N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Research Unit Analytical Pathology (AAP)
Institute of Structural Biology (STB)
CF Pathology & Tissue Analytics (CF-PTA)
POF-Topic(s) 30201 - Metabolic Health
30502 - Diabetes: Pathophysiology, Prevention and Therapy
30205 - Bioengineering and Digital Health
30203 - Molecular Targets and Therapies
30505 - New Technologies for Biomedical Discoveries
Research field(s) Helmholtz Diabetes Center
Enabling and Novel Technologies
PSP Element(s) G-502294-001
G-502200-005
G-500390-001
G-503000-001
G-502200-001
A-630600-001
DOI 10.1038/s41366-018-0221-z
WOS ID WOS:000470098400017
Scopus ID 85054374579
PubMed ID 30283080
Erfassungsdatum 2018-10-18
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