Proteomic analysis of rat hypothalamus revealed the role of ubiquitin-proteasome system in the genesis of DR or DIO.

Obesity has become a global epidemic, contributing to the increasing burdens of cardiovascular disease and type 2 diabetes. However, the precise molecular mechanisms of obesity remain poorly elucidated. The hypothalamus plays a major part in regulating energy homeostasis by integrating all kinds of nutritional signals. This study investigated the hypothalamus protein profile in diet-induced obese (DIO) and diet-resistant (DR) rats using two dimensional gel electrophoresis (2-DE) combined with MALDI-TOF/TOF-MS analysis. Twenty-two proteins were identified in the hypothalamus of DIO or DR rats. These include metabolic enzymes, antioxidant proteins, proteasome related proteins, and signaling proteins, some of which are related to AMP-activated protein kinase (AMPK) signaling or mitochondrial respiration. Among these proteins, in comparison with the normal-diet group, Ubiquitin was significantly decreased in DR rats but not changed in DIO rats, while Ubiquitin carboxyl-terminal esterase L1 (UCHL-1) was decreased in DIO rats but not changed in DR rats. The expression level of Ubiquitin and UCHL-1 were further validated using Western blot analysis. Our study reveals that Ubiquitin and UCHL-1 are obesity-related factors in the hypothalamus that may play an important role in the genesis of DR or DIO by interfering with the integrated signaling network that control energy balance and feeding.