The rates of obesity and type II diabetes are rising at an alarming rate worldwide, highlighting the pressing need to understand the molecular events underlying these pathological conditions. Cellular signaling pathways within key areas of the central nervous system have been identified that mediate a multitude of metabolic processes, including the leptin, insulin and brain-derived neurotrophic factor (BDNF) signaling pathways. Disruption of the rapid reversible phosphorylation events critical for regulation of these CNS signaling pathways alter their influence on energy balance and glucose homeostasis, thereby contributing to the pathogenesis of obesity and diabetes. Several protein tyrosine phosphatases (PTPs) have been identified as important regulators of central leptin signaling, yet how these PTPs cooperate dynamically to regulate leptin signaling or alternative signaling pathways that regulate energy balance remains unclear. The protein tyrosine phosphatase 1B (PTP1B) is an important regulator of leptin signaling and CNS control of metabolism;mice with whole brain or neuron-specific deficiency of PTP1B are lean and leptin hypersensitive, and display increased energy expenditure and improved glucose homeostasis. Recently, the tyrosine phosphatase epsilon (RPTPe) was also shown to be negative regulator of leptin signaling, raising the interesting possibility that PTP1B and RPTPe-deficiency may have synergistic beneficial metabolic effects. In this proposal the effects of compound PTP1B- and RPTPe-deficiency on leptin signaling, energy balance and glucose homeostasis will be assessed. Notably, in preliminary studies we identify the TrkB receptor as a novel substrate of PTP1B and show that PTP1B-/- mice display enhanced metabolic responses to central BDNF delivery. Thus, we will test the novel hypothesis that PTP1B is a physiologically relevant regulator of the BDNF signaling pathway at specific CNS sites in vivo and that PTP1B-deficiency will enhance BDNF/TrkB signaling and lead to improved energy balance. Finally, PTP1B expression is elevated in the brain of obese rodents;however, it is not clear whether increased central PTP1B per se promotes obesity and glucose intolerance, or which key brain regions and signaling pathways are involved. A novel mouse model of inducible PTP1B expression will be utilized to test the hypothesis that targeted neuronal induction of PTP1B expression within key CNS sites will promote obesity and impair glucose tolerance. Overall the proposed research will provide substantial new insight into the metabolic functions of protein tyrosine phosphatases in key CNS metabolic signaling pathways, and is highly relevant to the treatment of human obesity and type II diabetes.
Given that obesity and diabetes are increasing at an alarming rate throughout the world, there is an urgent need to understand the mechanisms underlying these diseases in order to develop novel therapeutic strategies. The proposed experiments will investigate cellular mechanisms within the brain that may contribute to the development of obesity and type II diabetes. This research is relevant to public health as the increasing prevalence of obesity and diabetes is leading to a tremendous global health crisis and a significant burden on our healthcare system.
|Ozek, Ceren; Kanoski, Scott E; Zhang, Zhong-Yin et al. (2014) Protein-tyrosine phosphatase 1B (PTP1B) is a novel regulator of central brain-derived neurotrophic factor and tropomyosin receptor kinase B (TrkB) signaling. J Biol Chem 289:31682-92|
|Tsou, Ryan C; Rak, Kimberly S; Zimmer, Derek J et al. (2014) Improved metabolic phenotype of hypothalamic PTP1B-deficiency is dependent upon the leptin receptor. Mol Metab 3:301-12|
|De Jonghe, Bart C; Hayes, Matthew R; Bence, Kendra K (2011) Melanocortin control of energy balance: evidence from rodent models. Cell Mol Life Sci 68:2569-88|
|Loh, Kim; Fukushima, Atsushi; Zhang, Xinmei et al. (2011) Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metab 14:684-99|
|Agouni, Abdelali; Mody, Nimesh; Owen, Carl et al. (2011) Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress. Biochem J 438:369-78|
|De Jonghe, Bart C; Hayes, Matthew R; Banno, Ryoichi et al. (2011) Deficiency of PTP1B in POMC neurons leads to alterations in energy balance and homeostatic response to cold exposure. Am J Physiol Endocrinol Metab 300:E1002-11|
|Hayes, Matthew R; Leichner, Theresa M; Zhao, Shiru et al. (2011) Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation. Cell Metab 13:320-30|
|Banno, Ryoichi; Zimmer, Derek; De Jonghe, Bart C et al. (2010) PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. J Clin Invest 120:720-34|