Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism.
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 CaMKIIalpha-Cre transgenic mice with a conditional Shp2 mutant (Shp2(flox)) strain. Surprisingly, a prominent phenotype of the mutant (CaMKIIalpha-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.
Zhang
Eric E
EE
Program in Signal Transduction, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Chapeau
Emilie
E
Hagihara
Kazuki
K
Feng
Gen-Sheng
GS
D000818:Animals; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D004734:Energy Metabolism; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D007031:Hypothalamus / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology* / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D010641:Phenotype; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse