Protein Tyrosine Phosphatase Epsilon as a Regulator of Body Weight and Glucose Metabolism

The obesity pandemic has focused attention in recent years to the physiological and molecular mechanisms that regulate body weight and glucose metabolism. Key signaling pathways that regulate both parameters depend heavily on reversible phosphorylation of proteins on tyrosine residues, a process regulated by the opposing activities of tyrosine kinases and tyrosine phosphatases. Here we review the roles of protein tyrosine phosphatase epsilon (PTPe) in regulating the leptin and insulin signaling pathways and through them—body weight and glucose metabolism. Mice lacking PTPe are leptin-hypersensitive and are protected from weight gain that follows a high-fat diet. PTPe helps downregulate leptin receptor signaling in the hypothalamus by dephosphorylating JAK2 following activation of the leptin receptor, thus inhibiting the receptor post-activation. PTPe is induced to perform this function after undergoing leptin receptor-induced phosphorylation at its C-terminal Y695. Mice lacking PTPe are also insulin-hypersensitive, indicating that PTPe downregulates signaling by this receptor as well. Studies in muscle cells confirm that PTPe inhibits insulin receptor signaling, possibly by targeting the receptor itself. These studies identify PTPe as a physiological inhibitor of both signaling pathways and as a factor in supporting the resistance to leptin and insulin that is established in obesity and in type-II diabetes, respectively.