The Role Of Protein Tyrosine Phosphatase 1b In The Central Regulation Of Energy Homeostasis

Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed tyrosine phosphatase implicated in the central control of energy homeostasis via negative regulation of leptin signaling. Mice with central nervous system (CNS)-specific PTP1B deficiency demonstrate clear metabolic improvements, including decreased body weight and adiposity presumably due to enhanced leptin sensitivity. Interestingly, compound PTP1B:leptin double mutants show attenuated weight gain compared to leptin single mutants, suggesting that the metabolic effects of PTP1B deficiency may also involve non-leptin signaling pathways. Indeed, insulin and other non-leptin cytokines, such as interleukin-6, have been implicated in the CNS control of energy balance, and these pathways are also candidates of PTP1B regulation. Thus, whether or not the metabolic effects of PTP1B deficiency are due exclusively to enhanced leptin signaling remains unclear. This dissertation examines the role of central PTP1B in the control of leptin receptor-dependent energy homeostasis. A leptin receptor-expressing cell specific PTP1B-deficient (LepRb PTP1B / ) mouse model was generated and its metabolic phenotype was analyzed in comparison to wildtype controls and to whole body PTP1B knockouts. Though subtle phenotypic differences between LepRb-PTP1B-/- and PTP1B-/- mice exist, LepRb-PTP1B-/- mice demonstrate a majority of the phenotype observed in whole body PTP1B knockouts, including decreased body weight and adiposity and improved leptin sensitivity compared to wildtype controls. To further elucidate whether or not central PTP1B regulates non-leptin signaling pathways, a compound hypothalamic PTP1B:LepRb double mutant (Nkx2.1-PTP1B-/-:LepRb-/-) was generated and metabolically phenotyped in comparison to hypothalamic leptin receptor (Nkx2.1-LepRb-/-) and PTP1B (Nkx2.1-PTP1B-/-) mutant mice. While Nkx2.1-PTP1B-/- mice show decreased body weight and adiposity compared to wildtypes, both Nkx2.1-PTP1B-/-:LepRb /- and Nkx2.1-LepRb-/- show a severe obese phenotype marked by similarly increased weight gain, total fat mass, food intake, and glucose intolerance, indicating that the metabolic benefits of hypothalamic PTP1B deficiency are dependent upon functional leptin receptor signaling. Finally, whether PTP1B can regulate interleukin-6 signaling was explored using an immortalized mouse hypothalamic cell line. In summary, these data show that PTP1B is a critical regulator of energy balance within leptin receptor-expressing cells and within the hypothalamus specifically, and further begin to unravel the signaling pathways mediating the beneficial metabolic effects of central PTP1B deficiency.