Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism

EE Zhang, E Chapeau, K Hagihara… - Proceedings of the …, 2004 - National Acad Sciences
EE Zhang, E Chapeau, K Hagihara, GS Feng
Proceedings of the National Academy of Sciences, 2004National Acad Sciences
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 …
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.
National Acad Sciences