Oops! I Cut It Again: Modulatory Proteolysis in Metabolic Health and Disease

Proteolysis is an irreversible posttranslational modification that modulates protein stability, localization, interactions, and function. There are four intracellular proteolytic systems (calpains, caspases, ubiquitin-proteasome system, and lysosomes) and several extracellular proteases (metalloproteases and serine proteases). In this work, we review the diverse effects of proteolysis on the physiology of tissues vital for metabolic homeostasis as well as the contribution of proteolytic systems to the development of metabolic diseases. Proteolytic systems regulate processes essential for maintaining metabolic homeostasis, including insulin secretion, insulin sensitivity and glucose uptake, adipose tissue physiology, muscle mass, and lipid metabolism in the liver. Concordantly, dysregulation of these systems contributes to the development of metabolic diseases, such as metabolic syndrome, insulin resistance, obesity, sarcopenia, and metabolic dysfunction-associated steatotic liver disease, acting both as causal and aggravating factors.