Protein tyrosine phosphatase 1B (PTP1B) and SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) have been shown in mice to regulate metabolism via the central nervous system, but the specific neurons mediating these effects are unknown. Here, we have shown that proopiomelanocortin (POMC) neuronspecific deficiency in PTP1B or SHP2 in mice results in reciprocal effects on weight gain, adiposity, and energy balance induced by high-fat diet. Mice with POMC neuron-specific deletion of the gene encoding PTP1B (referred to herein as POMC-Ptp1b -/-mice) had reduced adiposity, improved leptin sensitivity, and increased energy expenditure compared with wild-type mice, whereas mice with POMC neuron-specific deletion of the gene encoding SHP2 (referred to herein as POMC-Shp2 -/-mice) had elevated adiposity, decreased leptin sensitivity, and reduced energy expenditure. POMC-Ptp1b -/-mice showed substantially improved glucose homeostasis on a high-fat diet, and hyperinsulinemic-euglycemic clamp studies revealed that insulin sensitivity in these mice was improved on a standard chow diet in the absence of any weight difference. In contrast, POMCShp2 -/-mice displayed impaired glucose tolerance only secondary to their increased weight gain. Interestingly, hypothalamic Pomc mRNA and α-melanocyte-stimulating hormone (αMSH) peptide levels were markedly reduced in POMC-Shp2 -/-mice. These studies implicate PTP1B and SHP2 as important components of POMC neuron regulation of energy balance and point to what we believe to be a novel role for SHP2 in the normal function of the melanocortin system. IntroductionObesity has become a major health concern worldwide (1). Currently there are few effective therapies for targeting obesity and its associated comorbidities in humans. The CNS has long been implicated in the control of energy balance, with the hypothalamus playing a key role as an integrator of metabolic information (reviewed in ref. 2). Thus, an important area of obesity research centers on understanding the neural signaling pathways that control energy balance.Within the hypothalamus, first-order neurons in the arcuate nucleus (ARC) respond to circulating adiposity signals, such as insulin and leptin, and project to second-order neurons in the paraventricular nucleus (PVN), the dorsomedial hypothalamus (DMH), and the lateral hypothalamus (LHA) to mediate effects on food intake and energy expenditure (3-7). Two distinct populations of first-order neurons synthesize either agouti-related protein (AgRP) or proopiomelanocortin (POMC) and mediate opposing effects on energy balance (4,8). The POMC precursor is cleaved into biologically active peptides, including α-melanocyte-stimulating hormone (αMSH), which binds to melanocortin-3 and -4 receptors on target second-order neurons (9). The adipocyte-secreted hormone leptin acts in the brain as a catabolic hormone to decrease appetite and increase energy expenditure via simultaneous suppression of AgRP neurons and stimulation of POMC neurons (4, 10, 11).The discovery of leptin init...

ER-bound PTP1B is expressed in hippocampal neurons, and accumulates among neurite contacts. PTP1B dephosphorylates ß-catenin in N-cadherin complexes ensuring cell-cell adhesion. Here we show that endogenous PTP1B, as well as expressed GFP-PTP1B, are present in dendritic spines of hippocampal neurons in culture. GFP-PTP1B overexpression does not affect filopodial density or length. In contrast, impairment of PTP1B function or genetic PTP1B-deficiency leads to increased filopodia-like dendritic spines and a reduction in mushroom-like spines, while spine density is unaffected. These morphological alterations are accompanied by a disorganization of pre- and post-synapses, as judged by decreased clustering of synapsin-1 and PSD-95, and suggest a dynamic synaptic phenotype. Notably, levels of ß-catenin-Tyr-654 phosphorylation increased ∼5-fold in the hippocampus of adult PTP1B−/− (KO) mice compared to wild type (WT) mice and this was accompanied by a reduction in the amount of ß-catenin associated with N-cadherin. To determine whether PTP1B-deficiency alters learning and memory, we generated mice lacking PTP1B in the hippocampus and cortex (PTP1Bfl/fl–Emx1-Cre). PTP1Bfl/fl–Emx1-Cre mice displayed improved performance in the Barnes maze (decreased time to find and enter target hole), utilized a more efficient strategy (cued), and had better recall compared to WT controls. Our results implicate PTP1B in structural plasticity within the hippocampus, likely through modulation of N-cadherin function by ensuring dephosphorylation of ß-catenin on Tyr-654. Disruption of hippocampal PTP1B function or expression leads to elongation of dendritic filopodia and improved learning and memory, demonstrating an exciting novel role for this phosphatase.