Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity.
Obesity is a major public health problem and is often associated with type 2 diabetes mellitus, cardiovascular disease, and metabolic syndrome. Leptin is the crucial adipostatic hormone that controls food intake and body weight through the activation of specific leptin receptors (OB-R) in the hypothalamic arcuate nucleus (ARC). However, in most obese patients, high circulating levels of leptin fail to bring about weight loss. The prevention of this "leptin resistance" is a major goal for obesity research. We report here a successful prevention of diet-induced obesity (DIO) by silencing a negative regulator of OB-R function, the OB-R gene-related protein (OB-RGRP), whose transcript is genetically linked to the OB-R transcript. We provide in vitro evidence that OB-RGRP controls OB-R function by negatively regulating its cell surface expression. In the DIO mouse model, obesity was prevented by silencing OB-RGRP through stereotactic injection of a lentiviral vector encoding a shRNA directed against OB-RGRP in the ARC. This work demonstrates that OB-RGRP is a potential target for obesity treatment. Indeed, regulators of the receptor could be more appropriate targets than the receptor itself. This finding could serve as the basis for an approach to identifying potential new therapeutic targets for a variety of diseases, including obesity.
Departments of Cell Biology and Hematology, Institut Cochin, Unité Mixte de Recherche 8104, Centre National de la Recherche Scientifique, Université Paris Descartes, 75014 Paris, France.
Cyril
C
Couturier
Chamsy
C
Sarkis
Karin
K
Séron
Sandrine
S
Belouzard
Patty
P
Chen
Aude
A
Lenain
Laetitia
L
Corset
Julie
J
Dam
Virginie
V
Vauthier
Anne
A
Dubart
Jacques
J
Mallet
Philippe
P
Froguel
Yves
Y
Rouillé
Ralf
R
Jockers
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D007031:Hypothalamus / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D016086:Lentivirus / Q000235:genetics; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism / Q000517:prevention & control*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D002352:Carrier Proteins; D004041:Dietary Fats; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; C484581:Obrgrp protein, mouse; D016376:Oligonucleotides, Antisense; D054411:Receptors, Leptin; D049452:Green Fluorescent Proteins