title: The LIM domain only 4 protein is a metabolic responsive inhibitor of protein tyrosine phosphatase 1B that controls hypothalamic leptin signaling.
abstract: Protein tyrosine phosphatase 1B (PTP1B) counteracts leptin signaling and is a therapeutic target for obesity and diabetes. Here we found that LIM domain only 4 (LMO4) inhibits PTP1B activity by increasing the oxidized inactive form of PTP1B. Mice with neuronal ablation of LMO4 have elevated PTP1B activity and impaired hypothalamic leptin signaling, and a PTP1B inhibitor normalized PTP1B activity and restored leptin control of circulating insulin levels. LMO4 is palmitoylated at its C-terminal cysteine, and deletion of this residue prevented palmitoylation and retention of LMO4 at the endoplasmic reticulum and abolished its inhibitory effect on PTP1B. Importantly, LMO4 palmitoylation is sensitive to metabolic stress; mice challenged with a brief high-fat diet or acute intracerebroventricular infusion of saturated fatty acid had less palmitoylated LMO4, less oxidized PTP1B, and increased PTP1B activity in the hypothalamus. Thus, unleashed PTP1B activity attributable to loss of LMO4 palmitoylation may account for rapid loss of central leptin signaling after acute exposure to saturated fat.
authors.affiliation: Ottawa Hospital Research Institute, Centre for Stroke Recovery, Ottawa, Ontario, Canada K1Y 4E9.
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Pandey
authors.forename: Xun
authors.initials: X
authors.lastname: Zhou
authors.forename: Zhaohong
authors.initials: Z
authors.lastname: Qin
authors.forename: Tariq
authors.initials: T
authors.lastname: Zaman
authors.forename: Mariana
authors.initials: M
authors.lastname: Gomez-Smith
authors.forename: Kianoosh
authors.initials: K
authors.lastname: Keyhanian
authors.forename: Hymie
authors.initials: H
authors.lastname: Anisman
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Brunel
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.forename: Hsiao-Huei
authors.initials: HH
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D002776:Cholestanes / Q000008:administration & dosage; D004721:Endoplasmic Reticulum / Q000187:drug effects; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D007031:Hypothalamus / Q000378:metabolism* / Q000648:ultrastructure; D066298:In Vitro Techniques; D057967:Infusions, Intraventricular; D007333:Insulin Resistance; D060588:LIM Domain Proteins / Q000172:deficiency / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013096:Spermine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: C441128:3-N-1(spermine)-7, 24-dihydroxy-5-cholestane 24-sulfate; D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins; D002776:Cholestanes; D060588:LIM Domain Proteins; D020738:Leptin; C491976:Lmo4 protein, mouse; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria; D013096:Spermine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D009638:Norepinephrine
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