Proteases play multifaceted roles in regulating inflammation and metabolism via proteolytic cleavage of proteins, or by directly activating receptors. We have found certain serine proteases upregulate transient increases in systemic blood glucose in mice. These proteases share the common property of activating the G protein-coupled receptor protease activated receptor 2 (PAR2), with PAR2 deficient mice being resistant to protease-induced hyperglycemia. Mouse hepatic tissue and primary hepatocytes demonstrated that PAR2 activation directly regulates glycogenolysis in the liver to produce glucose. Administration of serine proteases also resulted in a PAR2-dependent upregulation of inflammatory cells and cytokines in the mouse liver. PAR2 antagonism or glycolytic inhibition with 2-deoxy-ᴅ-glucose prevents induction of certain inflammatory mediators in the liver, suggesting protease induced inflammation is dependent on both glucose availability and PAR2 signaling. This presentation highlights PAR2-activating proteases and peptide agonists as novel mediators of metabolic dysfunction, promoting glycogenolysis that drives sterile inflammation. This constitutes a new link between extracellular proteases, glucose metabolism and tissue inflammation for maintenance of homeostasis.