Defective Regulation of the Ubiquitin/Proteasome System in the Hypothalamus of Obese Male Mice

In both human and experimental obesity, inflammatory damage to the hypothalamus plays an important role in the loss of the coordinated control of food intake and energy expenditure. Upon prolonged maintenance of increased body mass, the brain changes the defended set point of adiposity, and returnin...

Full description

Saved in:
Bibliographic Details
Published in:Endocrinology (Philadelphia) 2014-08, Vol.155 (8), p.2831-2844
Main Authors: Ignacio-Souza, Leticia M, Bombassaro, Bruna, Pascoal, Livia B, Portovedo, Mariana A, Razolli, Daniela S, Coope, Andressa, Victorio, Sheila C, de Moura, Rodrigo F, Nascimento, Lucas F, Arruda, Ana P, Anhe, Gabriel F, Milanski, Marciane, Velloso, Licio A
Format: Article
Language:English
Subjects:
Animals
Autophagy
Diet, High-Fat
Disease Models, Animal
Humans
Hypothalamus - metabolism
Male
Mice
Mice, Inbred C3H
Microglia - metabolism
Neurons - metabolism
Obesity - metabolism
Phenotype
Proteasome Endopeptidase Complex - metabolism
Transcription Factors - metabolism
Ubiquitin - metabolism
Weight Gain
Weight Loss
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In both human and experimental obesity, inflammatory damage to the hypothalamus plays an important role in the loss of the coordinated control of food intake and energy expenditure. Upon prolonged maintenance of increased body mass, the brain changes the defended set point of adiposity, and returning to normal weight becomes extremely difficult. Here we show that in prolonged but not in short-term obesity, the ubiquitin/proteasome system in the hypothalamus fails to maintain an adequate rate of protein recycling, leading to the accumulation of ubiquitinated proteins. This is accompanied by an increased colocalization of ubiquitin and p62 in the arcuate nucleus and reduced expression of autophagy markers in the hypothalamus. Genetic protection from obesity is accompanied by the normal regulation of the ubiquitin/proteasome system in the hypothalamus, whereas the inhibition of proteasome or p62 results in the acceleration of body mass gain in mice exposed for a short period to a high-fat diet. Thus, the defective regulation of the ubiquitin/proteasome system in the hypothalamus may be an important mechanism involved in the progression and autoperpetuation of obesity.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2014-1090