Abnormal splicing of the leptin receptor in diabetic mice

Lee, Gwo-Hwa; Proenca, R.; Montez, J. M.; Carroll, K. M.; Darvishzadeh, J. G.; Lee, J. I.; Friedman, J. M.

doi:10.1038/379632a0

Cited by 2,327Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesHypothalamic control of reproductive hormones

Abnormal splicing of the leptin receptor in diabetic mice

Lee, Gwo-Hwa, Proenca, R., Montez, J. M., Carroll, K. M., Darvishzadeh, J. G., Lee, J. I., Friedman, J. M.·1996·Nature

DOI 10.1038/379632a0

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Abstract

Mutations in the mouse diabetes (db) gene result in obesity and diabetes in a syndrome resembling morbid human obesity. Previous data suggest that the db gene encodes the receptor for the obese (ob) gene product, leptin. A leptin receptor was recently cloned from choroid plexus and shown to map to the same 6-cM interval on mouse chromosome 4 as db. This receptor maps to the same 300-kilobase interval as db, and has at least six alternatively spliced forms. One of these splice variants is expressed at a high level in the hypothalamus, and is abnormally spliced in C57BL/Ks db/db mice. The mutant protein is missing the cytoplasmic region, and is likely to be defective in signal transduction. This suggests that the weight-reducing effects of leptin may be mediated by signal transduction through a leptin receptor in the hypothalamus.

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Leptin receptor RNA was alternatively spliced and only one of the splice variants, referred to as ObRb at the time (also known as LepR-l), was mutant in C57Bl/Ks db/db mice.
“It was subsequently shown that leptin receptor RNA was alternatively spliced and that only one of the splice variants, referred to as ObRb at the time (also known as LepR-l), was mutant in C57Bl/Ks db/db mice (25,26).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [25]
ObRb is the only receptor isoform that expresses all the protein motifs required for cytokine receptor signaling.
“ObRb is the only receptor isoform that expresses all the protein motifs required for cytokine receptor signaling.”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [25]
These mutant mice show an identical phenotype to animals with null mutations of the leptin receptor or leptin itself.
“These mutant mice show an identical phenotype to animals with null mutations of the leptin receptor or leptin itself (25,26).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [25]
ObRb was highly enriched in the hypothalamus in precisely those nuclei that alter body weight when lesioned.
“ObRb was highly enriched in the hypothalamus in precisely those nuclei that alter body weight when lesioned (25,27).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [25]
Mice lacking only LepRb exhibit a phenotype similar to leptin-deficient ob/ob mice.
“mice that lack only LepRb (e.g. db/db mice) exhibit a phenotype similar to leptin-deficient ob/ob mice (100).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [100]

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Authors: Lee, G.-H., Proenca, R., Montez, J. M., Carroll, K. M., Darvishzadeh, J. G., Lee, J. I., & Friedman, J. M.
Affiliations: Howard Hughes Medical Institute (US)
Rockefeller University (US)
ORCID: Friedman, J. M.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1996-02
Volume: 379
Issue: 6566
Pages: 632-635
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/379632a0
OpenAlex: W2016994959
Cited by: 2,327
References: 27
Citations by year: 2026: 12 · 2025: 22 · 2024: 17 · 2023: 20 · 2022: 36 · 2021: 46 · 2020: 35 · 2019: 47 · 2018: 38 · 2017: 46 · 2016: 58 · 2015: 62 · 2014: 88 · 2013: 88 · 2012: 83
FWCI: 56.95
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords: leptin receptor, alternative splicing, db/db mice, obesity, leptin, signal transduction, hypothalamus, obesity-related genes, chromosome 4, cytoplasmic domain, body weight regulation
MeSH terms: Amino Acid Sequence, Animals, Base Sequence, Carrier Proteins, Chromosome Mapping, Diabetes Mellitus, Experimental, Mice, Inbred C57BL, Molecular Sequence Data, Mutation, Proteins, Receptors, Cell Surface, Tissue Distribution, Polymerase Chain Reaction, Alternative Splicing, DNA Primers, Leptin, Mice, Receptors, Leptin

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Abnormal splicing of the leptin receptor in diabetic mice

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