The proteasome regulates body weight and systemic nutrient metabolism during fasting.

The ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway are the primary means of degradation in mammalian tissues. We sought to determine the individual contribution of the UPS and autophagy to tissue catabolism during fasting. Mice were overnight fasted for 15 h before regaining food access ("Fed" group, = 6) or continuing to fast ("Fast" group, = 7) for 3 h. In addition, to investigate the effects of autophagy on systemic metabolism and tissue degradation, one group of mice was fasted for 18 h and treated with chloroquine ("Fast + CLQ" group, = 7) and a fourth group of mice was treated with bortezomib ("Fast + Bort" group, = 7) to assess the contribution of the UPS. Body weight, tissue weight, circulating hormones and metabolites, intracellular signaling pathways, and protein synthesis were investigated. Fasting induced the loss of body weight, liver mass, and white adipose tissue in the Fast and the Fast + CLQ group, whereas the Fast + Bort group maintained tissue and body weight. Fasting reduced glucose and increased β hydroxybutyrate in the circulation of all mice. Both changes were most profound in the Fast + Bort group compared with the other fasting conditions. Molecular signaling indicated a successful inhibition of hepatic UPS with bortezomib and an upregulation of the PI3K/AKT/mTOR pathway. The latter was further supported by an increase in hepatic protein synthesis with bortezomib. Inhibition of the UPS through bortezomib blocks body weight loss and tissue catabolism during an acute overnight fast in mice. The effects were likely mediated through a combined effect of the drug on biomolecule degradation and synthesis. Bortezomib treatment prevents tissue and body weight loss during fasting. The loss of proteasome activity with bortezomib exacerbates fasting-induced ketogenesis. During fasting, bortezomib increases AMPK and PI3K/AKT signaling in the liver, which promotes protein synthesis.