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

2014; Oxford University Press; Volume: 155; Issue: 8 Linguagem: Inglês

10.1210/en.2014-1090

1945-7170

Letícia Martins Ignácio-Souza, Bruna Bombassaro, Lívia Bitencourt Pascoal, Mariana Portovedo, Daniela S. Razolli, Andressa Coope, Sheila C. Victório, Rodrigo Ferreira de Moura, Lucas F. Nascimento, Ana Paula Arruda, Gabriel Forato Anhê, Marciane Milanski, Lı́cio A. Velloso,

Sirtuins and Resveratrol in Medicine

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.