Regional roles of central TRKB receptors in energy balance and regulation by PTP1B / Ceren Ozek.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Ozek, Ceren, author.

Contributor:

Bence, Kendra K., degree supervisor.

Kalb, Robert G., degree committee member.

Grill, Harvey J., 1948- degree committee member.

DeJonghe, Bart C., degree committee member.

Reyes, Teresa M., degree committee member.

University of Pennsylvania. Department of Neuroscience.

Language:

English

Subjects (All):

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Local Subjects:

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Physical Description:

xii, 150 leaves : illustrations (some color) ; 29 cm

Production:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2015.

Summary:

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 diet-induced 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.

Notes:

Ph. D. University of Pennsylvania 2015.

Department: Neuroscience.

Supervisor: Kendra K. Bence.

Includes bibliographical references.

OCLC:

945583649