Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism
AUTOR(ES)
Zhang, Eric E.
FONTE
National Academy of Sciences
RESUMO
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 (Shp2flox) strain. Surprisingly, a prominent phenotype of the mutant (CaMKIIα-Cre:Shp2flox/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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=528739Documentos Relacionados
- Morphogenetic movements at gastrulation require the SH2 tyrosine phosphatase Shp2
- Receptor-Specific Regulation of Phosphatidylinositol 3′-Kinase Activation by the Protein Tyrosine Phosphatase Shp2
- Tyrosine phosphatase SHP-2 is a mediator of activity-dependent neuronal excitotoxicity
- Binding of Shp2 Tyrosine Phosphatase to FRS2 Is Essential for Fibroblast Growth Factor-Induced PC12 Cell Differentiation
- Effect of tyrosine phosphatase Shp2 silencing on phenotypic changes of cardiomycytes and effect of mutations and deletion of Shp2 in the hearts of mjice subjected to mechanical stress