TY - JOUR
T1 - Protein tyrosine phosphatase epsilon affects body weight by downregulating leptin signaling in a phosphorylation-dependent manner
AU - Rousso Noori, Noori, Liat
AU - Knobler, Hilla
AU - Levy-Apter, Einat
AU - Kuperman, Yael
AU - Neufeld - Cohen, - Cohen, Adi
AU - Keshet, Yonat
AU - Akepati, Vasudheva R.
AU - Klinghoffer, Richard A.
AU - Chen, Alon
AU - Elson, Ari
N1 - Fritz Thyssen Stiftung, Germany; Weizmann Institute of ScienceWe thank Ms. Judith Hermesh, Ms. Golda Damari, Ms. Ofira Higfa, and Mr. Neria Sharabi for expert animal care. We also thank Prof. Edna Schechtman, Department of Industrial Engineering and Management, Ben Gurion University, Beer Sheva, Israel, for assistance with statistical analyses. We gratefully acknowledge the support of Dr. Benjamin Neel (Harvard Medical School and Ontario Cancer Institute), Dr. Nicholas Tonks (Cold Spring Harbor Laboratories), and Ceptyr, Inc., during the initial phase of this study. This study was funded by the Fritz Thyssen Stiftung, Germany. Support was also provided by the David and Fela Shapell Family Center for Genetic Disorders Research and by the Yeda Research and Development Co. Ltd., both of the Weizmann Institute of Science.
PY - 2011/5/4
Y1 - 2011/5/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79955599937&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2011.02.017
DO - 10.1016/j.cmet.2011.02.017
M3 - مقالة
SN - 1550-4131
VL - 13
SP - 562
EP - 572
JO - Cell Metabolism
JF - Cell Metabolism
IS - 5
ER -