The obese phenotypes of the diabetes (db) mouse and fatty (fa) rat are due to functional null mutations of the leptin receptor (Lepr). The recessive mutation in the Koletsky (f) obese rat maps to the same genetic intervals as db and fa and fails to complement the fa mutation. Comparison of the sequence of brain Lepr cDNA from +/+ and f/f animals reveals a T2349A transversion resulting in a Tyr763Stop nonsense mutation in the gene just before the transmembrane domain. Virtual absence of Lepr mRNA in whole brain from f/f animals is consistent with the presence of a null mutation. The predicted reduced cerebrospinal fluid (CSF) transport of leptin in both f/f and fa/fa mutants is reflected in the ∼10-fold lower ratio of CSF/plasma leptin concentration in the obese versus lean animals. However, equivalent CSF leptin concentration between lean and obese rats (fa/fa, f/f) indicates that leptin can enter the CSF through a non–Lepr-mediated mechanism, which may be saturated at normal physiological plasma leptin concentration.
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March 01 1997
Phenotype of the Obese Koletsky (f) Rat Due to Tyr763Stop Mutation in the Extracellular Domain of the Leptin Receptor (Lepr): Evidence for Deficient Plasma-to-CSF Transport of Leptin in Both the Zucker and Koletsky Obese Rat
X Sharon Wu-Peng;
X Sharon Wu-Peng
Laboratory of Human Behavior and Metabolism, Rockefeller University
New York, New York
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Streamson C Chua, Jr;
Streamson C Chua, Jr
Laboratory of Human Behavior and Metabolism, Rockefeller University
New York, New York
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Norichika Okada;
Norichika Okada
Laboratory of Human Behavior and Metabolism, Rockefeller University
New York, New York
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Shun-Mei Liu;
Shun-Mei Liu
Laboratory of Human Behavior and Metabolism, Rockefeller University
New York, New York
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Margery Nicolson;
Margery Nicolson
Amgen, Inc.
Thousand Oaks, California
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Rudolph L Leibel
Rudolph L Leibel
Laboratory of Human Behavior and Metabolism, Rockefeller University
New York, New York
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Address correspondence and reprint requests to Rudolph L. Leibel, MD, Laboratory of Human Behavior and Metabolism, Rockefeller University, 1230 York Ave., Box 181, New York, NY 10021. [email protected].
1
CSF, cerebrospinal fluid; EIA, enzyme immunoassay; Lepr, leptin receptor; nt, nucleotide; RT-PCR, reverse transcriptase polymerase chain reaction; SDS, sodium dodecyl sulfate; SSC, sodium chloride-sodium citrate.
Diabetes 1997;46(3):513–518
Article history
Received:
October 02 1996
Revision Received:
December 23 1996
Accepted:
December 23 1996
PubMed:
9032111
Citation
X Sharon Wu-Peng, Streamson C Chua, Norichika Okada, Shun-Mei Liu, Margery Nicolson, Rudolph L Leibel; Phenotype of the Obese Koletsky (f) Rat Due to Tyr763Stop Mutation in the Extracellular Domain of the Leptin Receptor (Lepr): Evidence for Deficient Plasma-to-CSF Transport of Leptin in Both the Zucker and Koletsky Obese Rat. Diabetes 1 March 1997; 46 (3): 513–518. https://doi.org/10.2337/diab.46.3.513
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