The increasing prevalence of obesity and co-morbidities such as type II diabetes poses a significant health problem worldwide. Understanding the cellular signaling pathways underlying these pathological states is critical to assist in developing potential therapeutic treatment of these conditions. Leptin is a hormone secreted by fat, which acts on neurons in the central nervous system (CNS) to regulate food intake and energy expenditure. Leptin initiates an intracellular signaling cascade which in turn leads to changes in ion channel activity and gene expression that ultimately keep energy balance in check. The leptin signaling pathway is tightly controlled by tyrosine phosphorylation, and two protein tyrosine phosphatases (PTPs) have recently been implicated in regulation of the leptin signaling pathway in the brain: PTP1B and SHP2. These PTPs clearly have important in vivo roles in regulating energy balance, but the precise neuronal site(s) of action and the mechanism of PTP1B/SHP2 action at a cellular level are unknown. POMC and AgRP neurons in the hypothalamus are an important site of both energy balance and glucose homeostasis regulation. We hypothesize that PTP1B and SHP2 have important metabolic roles specifically in these neurons via either leptin-dependent or - independent effects.
Our specific aims will address the effects of PTP1B or SHP2 deletion specifically in POMC- or AgRP-expressing neurons of mice on body weight, adiposity, leptin sensitivity, and glucose tolerance. Furthermore, these studies will address how PTP1B or SHP2 deletion in hypothalamic neurons affects the electrophysiological properties of these neurons. This combination of genetic, biochemical, and electrophysiological techniques will provide essential information about the cellular mechanism of PTP action in hypothalamic neurons as relates to energy balance.

Public Health Relevance

Obesity and associated diseases such as type II diabetes are increasing at an alarming rate throughout the world. These proposed experiments will investigate the cellular mechanisms contributing to the development of leptin resistance, a pathological state which can lead to obesity and type II diabetes. We hypothesize that regulation of signaling by protein tyrosine phosphatases in the hypothalamus is an important component of the cellular signaling pathways regulating neuronal control of energy balance.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Hyde, James F
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University of Pennsylvania
Veterinary Sciences
Schools of Veterinary Medicine
United States
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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