OBJECTIVE-The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling; consequently, mice deficient in PTP1B are hypersensitive to insulin. Because PTP1B Ϫ/Ϫ mice have diminished fat stores, the extent to which PTP1B directly regulates glucose homeostasis is unclear. Previously, we showed that brain-specific PTP1B Ϫ/Ϫ mice are protected against high-fat diet-induced obesity and glucose intolerance, whereas muscle-specific PTP1B Ϫ/Ϫ mice have increased insulin sensitivity independent of changes in adiposity. Here we studied the role of liver PTP1B in glucose homeostasis and lipid metabolism. RESEARCH DESIGN AND METHODS-We analyzed body mass/adiposity, insulin sensitivity, glucose tolerance, and lipid metabolism in liver-specific PTP1B Ϫ/Ϫ and PTP1Bfl/fl control mice, fed a chow or high-fat diet. RESULTS-Compared with normal littermates, liver-specific PTP1BϪ/Ϫ mice exhibit improved glucose homeostasis and lipid profiles, independent of changes in adiposity. Liver-specific PTP1B Ϫ/Ϫ mice have increased hepatic insulin signaling, decreased expression of gluconeogenic genes PEPCK and G-6-Pase, enhanced insulin-induced suppression of hepatic glucose production, and improved glucose tolerance. Liver-specific PTP1B Ϫ/Ϫ mice exhibit decreased triglyceride and cholesterol levels and diminished expression of lipogenic genes SREBPs, FAS, and ACC. Liver-specific PTP1B deletion also protects against high-fat diet-induced endoplasmic reticulum stress response in vivo, as evidenced by decreased phosphorylation of p38MAPK, JNK, PERK, and eIF2␣ and lower expression of the transcription factors C/EBP homologous protein and spliced X box-binding protein 1. CONCLUSIONS-Liver

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...

The existence of adult β-cell progenitors remains the most controversial developmental biology topic in diabetes research. It has been reported that β-cell progenitors can be activated by ductal ligation–induced injury of adult mouse pancreas and apparently act in a cell-autonomous manner to double the functional β-cell mass within a week by differentiation and proliferation. Here, we demonstrate that pancreatic duct ligation (PDL) does not activate progenitors to contribute to β-cell mass expansion. Rather, PDL stimulates massive pancreatic injury, which alters pancreatic composition and thus complicates accurate measurement of β-cell content via traditional morphometry methodologies that superficially sample the pancreas. To overcome this potential bias, we quantified β-cells from the entire pancreas and observed that β-cell mass and insulin content are totally unchanged by PDL-induced injury. Lineage-tracing studies using sequential administration of thymidine analogs, rat insulin 2 promoter–driven cre-lox, and low-frequency ubiquitous cre-lox reveal that PDL does not convert progenitors to the β-cell lineage. Thus, we conclude that β-cells are not generated in injured adult mouse pancreas.