Protein Tyrosine Phosphatase Epsilon Affects Body Weight by Downregulating Leptin Signaling in a Phosphorylation-Dependent Manner

SummaryMolecular-level understanding of body weight control is essential for combating obesity. We show that female mice lacking tyrosine phosphatase epsilon (RPTPe) are protected from weight gain induced by high-fat food, ovariectomy, or old age and exhibit increased whole-body energy expenditure and decreased adiposity. RPTPe-deficient mice, in particular males, exhibit improved glucose homeostasis. Female nonobese RPTPe-deficient mice are leptin hypersensitive and exhibit reduced circulating leptin concentrations, suggesting that RPTPe inhibits hypothalamic leptin signaling in vivo. Leptin hypersensitivity persists in aged, ovariectomized, and high-fat-fed RPTPe-deficient mice, indicating that RPTPe helps establish obesity-associated leptin resistance. RPTPe associates with and dephosphorylates JAK2, thereby downregulating leptin receptor signaling. Leptin stimulation induces phosphorylation of hypothalamic RPTPe at its C-terminal Y695, which drives RPTPe to downregulate JAK2. RPTPe is therefore an inhibitor of hypothalamic leptin signaling in vivo, and provides controlled negative-feedback regulation of this pathway following its activation.

► PTPe is a negative regulator of hypothalamic leptin signaling in vivo
► Leptin-induced phosphorylation of PTPe drives it to dephosphorylate JAK2
► Lack of PTPe in mice reduces obesity (females) and improves blood glucose control
► Inhibition of RPTPe may contribute to treating obesity and diabetes