Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism
Autor: | Kazuki Hagihara, Gen-Sheng Feng, Emilie A. Chapeau, Eric E. Zhang |
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Rok vydání: | 2004 |
Předmět: |
STAT3 Transcription Factor
Hypothalamo-Hypophyseal System medicine.medical_specialty Phosphatase Hypothalamus Down-Regulation Mice Transgenic Protein Tyrosine Phosphatase Non-Receptor Type 11 Receptors Cell Surface Protein tyrosine phosphatase Biology Mice Prosencephalon Proto-Oncogene Proteins Internal medicine medicine Animals Humans Obesity STAT3 Mice Knockout Neurons Multidisciplinary Leptin receptor Leptin Intracellular Signaling Peptides and Proteins Janus Kinase 2 Protein-Tyrosine Kinases Biological Sciences DNA-Binding Proteins Fatty Liver Mice Inbred C57BL Phenotype Endocrinology Forebrain Trans-Activators biology.protein Receptors Leptin Protein Tyrosine Phosphatases Signal transduction Energy Metabolism Signal Transduction Proto-oncogene tyrosine-protein kinase Src |
Zdroj: | Proceedings of the National Academy of Sciences. 101:16064-16069 |
ISSN: | 1091-6490 0027-8424 |
Popis: | Shp2, a Src homology 2-containing tyrosine phosphatase, has been implicated in a variety of growth factor or cytokine signaling pathways. However, it is conceivable that this enzyme acts predominantly in one pathway versus the others in a cell, depending on the cellular context. To determine the putative functions of Shp2 in the adult brain, we selectively deleted Shp2 in postmitotic forebrain neurons by crossing CaMKIIα-Cre transgenic mice with a conditional Shp2 mutant (Shp2 flox ) strain. Surprisingly, a prominent phenotype of the mutant (CaMKIIα-Cre:Shp2 flox/flox or CaSKO) mice was the development of early-onset obesity, with increased serum levels of leptin, insulin, glucose, and triglycerides. The mutant mice were not hyperphagic but developed enlarged and steatotic liver. Consistent with previous in vitro data, we found that Shp2 down-regulates Jak2/Stat3 (signal transducer and activator of transcription 3) activation by leptin in the hypothalamus. However, Jak2/Stat3 down-regulation is offset by a dominant Shp2 promotion of the leptin-stimulated Erk pathway, leading to induction rather than suppression of leptin resistance upon Shp2 deletion in the brain. Collectively, these results suggest that a primary function of Shp2 in postmitotic forebrain neurons is to control energy balance and metabolism, and that this phosphatase is a critical signaling component of leptin receptor ObRb in the hypothalamus. Shp2 shows potential as a neuronal target for pharmaceutical sensitization of obese patients to leptin action. |
Databáze: | OpenAIRE |
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