A spontaneous leptin receptor point mutation causes obesity and differentially affects leptin signaling in hypothalamic nuclei resulting in metabolic dysfunctions distinct from db/db mice.
Animals
Arcuate Nucleus of Hypothalamus
/ metabolism
Energy Metabolism
/ physiology
Female
Genetic Predisposition to Disease
Glucose
/ metabolism
Hypothalamus
/ metabolism
Leptin
/ metabolism
Male
Mice
Mice, Inbred C57BL
Neurons
/ metabolism
Obesity
/ genetics
Point Mutation
Receptors, Leptin
/ genetics
Signal Transduction
/ physiology
Arcuate nucleus
Dorsomedial nucleus
Energy expenditure
Glucose tolerance
Leptin receptor mutation
Ventromedial nucleus
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
30
01
2019
revised:
18
04
2019
accepted:
22
04
2019
pubmed:
12
5
2019
medline:
21
4
2020
entrez:
12
5
2019
Statut:
ppublish
Résumé
Leptin (Lep) plays a crucial role in controlling food intake and energy expenditure. Defective Lep/LepRb-signaling leads to fat accumulation, massive obesity, and the development of diabetes. We serendipitously noticed spontaneous development of obesity similar to LepR-deficient (db/db) mice in offspring from a C57BL/6J breeding and transmittance of the phenotype in a Mendelian manner. Candidate gene sequencing revealed a spontaneous point mutation in the LepRb gene. We investigated leptin responsiveness, leptin receptor signaling and metabolic phenotype of this novel LepRb mutant mouse variant. Overexpression and functional tests of the mutant LepRb in 3T3 cells. Measurement of leptin responsiveness in hypothalamic nuclei, glucose tolerance, food uptake and energy expenditure in the mutant mice. The mutation results in the exchange of a glycine for serine (G506S) and introduces an alternative splice acceptor which, when used, encodes for a protein with a 40aa deletion that is retained in the cytoplasm. LepRb signaling was abrogated in the hypothalamic ventromedial nucleus (VMN) and dorsomedial nucleus (DMN), but only partially reduced in the hypothalamic arcuate nucleus (ARC) of LepRb This study provides further insight into differences of the leptin responsiveness in VMN, DMN, and ARC and its metabolic consequences.
Identifiants
pubmed: 31076350
pii: S2212-8778(19)30100-0
doi: 10.1016/j.molmet.2019.04.010
pmc: PMC6601129
pii:
doi:
Substances chimiques
Leptin
0
Receptors, Leptin
0
leptin receptor, mouse
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
131-141Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.
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