msi-1436 and Body-Weight

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.

Topics: Adaptor Proteins, Signal Transducing; Adrenal Glands; Animals; Bacterial Proteins; Blood Pressure; Body Weight; Cell Line, Transformed; Cholestanes; Endoplasmic Reticulum; Glucose Tolerance Test; Homeostasis; Hypothalamus; In Vitro Techniques; Infusions, Intraventricular; Insulin Resistance; Leptin; LIM Domain Proteins; Luminescent Proteins; Mice; Mice, Knockout; Norepinephrine; Pancreas; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Signal Transduction; Spermine