title: Protein tyrosine phosphatase epsilon affects body weight by downregulating leptin signaling in a phosphorylation-dependent manner.
abstract: Molecular-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.
authors.affiliation: Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Rousso-Noori
authors.forename: Hilla
authors.initials: H
authors.lastname: Knobler
authors.forename: Einat
authors.initials: E
authors.lastname: Levy-Apter
authors.forename: Yael
authors.initials: Y
authors.lastname: Kuperman
authors.forename: Adi
authors.initials: A
authors.lastname: Neufeld-Cohen
authors.forename: Yonat
authors.initials: Y
authors.lastname: Keshet
authors.forename: Vasudheva R
authors.initials: VR
authors.lastname: Akepati
authors.forename: Richard A
authors.initials: RA
authors.lastname: Klinghoffer
authors.forename: Alon
authors.initials: A
authors.lastname: Chen
authors.forename: Ari
authors.initials: A
authors.lastname: Elson
mesh_terms: D000818:Animals; D001835:Body Weight; D002478:Cells, Cultured; D004036:Diet, Atherogenic; D015536:Down-Regulation; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D015151:Immunoblotting; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000097:blood / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D010766:Phosphorylation; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000502:physiology*; D054411:Receptors, Leptin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020738:Leptin; D054411:Receptors, Leptin; D053614:Janus Kinase 2; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D005947:Glucose