Regional Roles of Central Trkb Receptors in Energy Balance and Regulation by Ptp1b

Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed phosphatase implicated in energy balance regulation. CNS-specific PTP1B-deficiency results in a lean phenotype with resistance to dietinduced obesity. PTP1B antagonizes actions of leptin, which regulates central energy balance by suppressing food intake and elevating energy expenditure. Although the metabolic effects of PTP1B-deficiency have been largely attributed to improved leptin sensitivity, mice lacking both leptin and PTP1B weigh less compared to the mice lacking leptin only, suggesting leptin-independent metabolic effects of PTP1B-deficiency. Biochemical studies have identified tropomyosin receptor kinase B (TrkB) as a potential substrate for PTP1B. Since TrkB ligand brain-derived neurotrophic factor (BDNF) is a key player in energy balance, this dissertation tests the hypothesis that PTP1B is a physiological regulator of central BDNF/TrkB signaling and further examines the metabolic role of endogenous hypothalamic and hindbrain BDNF/TrkB signaling. To assess whether PTP1B is a physiological regulator of central BDNF/TrkB signaling, an immortalized human neuronal SH-SY5Y-TrkB cell line was utilized in biochemical studies in vitro, and a mouse model of global PTP1B-deficiency (Ptpn1-/-) was used to test the metabolic response to exogenous central BDNF delivery in vivo. In SH-SY5Y-TrkB cells, PTP1B overexpression and PTP1B inhibition impairs and augments TrkB signaling, respectively. Furthermore, PTP1B interacts with the BDNF-activated TrkB receptor. Ptpn1-/mice exhibit enhanced hypothalamic TrkB phosphorylation, and are hypersensitive to central BDNF-induced increase in core temperature. Whether Ptpn1-/mice show increased hypothalamic neurogenesis was explored through BrdU studies. To further elucidate the role of endogenous BDNF/TrkB signaling in central metabolic control, hypothalamus (Nkx2.1-Ntrk2-/-) or hindbrain (Phox2b-Ntrk2+/-) specific TrkB-deficient mice were generated and their metabolic phenotype was analyzed in comparison to wild type controls. Nkx2.1-Ntrk2-/mice display increased body weight and adiposity due to alterations in food intake and energy expenditure, and have glucose homeostasis impairments. Interestingly, female mice lacking TrkB in the hypothalamus have a more robust metabolic phenotype. Phox2b-Ntrk2+/mice exhibit pronounced hyperphagia despite the absence of a body weight phenotype. In summary, these data clearly establish PTP1B as a novel, physiological regulator of central BDNF/TrkB signaling, and that endogenous hypothalamic and hindbrain TrkB signaling are essential to central metabolic control. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Neuroscience First Advisor Kendra K. Bence This dissertation is available at ScholarlyCommons: http://repository.upenn.edu/edissertations/1927 Subject Categories Neuroscience and Neurobiology This dissertation is available at ScholarlyCommons: http://repository.upenn.edu/edissertations/1927 REGIONAL ROLES OF CENTRAL TRKB RECEPTORS IN ENERGY BALANCE AND REGULATION BY PTP1B Ceren Ozek A DISSERTATION in Neuroscience Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2015 Supervisor of Dissertation ______________________ Kendra K. Bence, Associate Professor of Biomedical Sciences Graduate Group Chairperson ______________________ Joshua I. Gold, Professor of Neuroscience Dissertation Committee Robert G. Kalb (Chair), Professor of Neurology Harvey J. Grill, Professor of Psychology Bart C. DeJonghe, Assistant Professor of Biobehavioral and Health Sciences Teresa M. Reyes, Associate Professor of Psychiatry and Behavioral Neuroscience REGIONAL ROLES OF CENTRAL TRKB RECEPTORS IN ENERGY BALANCE AND REGULATION BY PTP1B COPYRIGHT 2015 Ceren Ozek