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2. Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance.

Author

Loh K, Fukushima A, Zhang X, Galic S, Briggs D, Enriori PJ, Simonds S, Wiede F, Reichenbach A, Hauser C, Sims NA, Bence KK, Zhang S, Zhang ZY, Kahn BB, Neel BG, Andrews ZB, Cowley MA, and Tiganis T

Subjects
Animals, Blood Glucose analysis, Body Composition drug effects, Diet, High-Fat, Enzyme Inhibitors pharmacology, Female, Gene Expression, Hypothalamus cytology, Infusions, Intraventricular, Insulin blood, Male, Mice, Mice, Transgenic, Neurons cytology, Obesity genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 1 antagonists & inhibitors, Protein Tyrosine Phosphatase, Non-Receptor Type 1 genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 2 antagonists & inhibitors, Protein Tyrosine Phosphatase, Non-Receptor Type 2 genetics, Receptors, Leptin metabolism, Tissue Culture Techniques, Hypothalamus metabolism, Leptin metabolism, Neurons metabolism, Obesity metabolism, Protein Tyrosine Phosphatase, Non-Receptor Type 1 deficiency, Protein Tyrosine Phosphatase, Non-Receptor Type 2 deficiency, Signal Transduction
Abstract

In obesity, anorectic responses to leptin are diminished, giving rise to the concept of "leptin resistance." Increased expression of protein tyrosine phosphatase 1B (PTP1B) has been associated with the attenuation of leptin signaling and development of cellular leptin resistance. Here we report that hypothalamic levels of the tyrosine phosphatase TCPTP are also elevated in obesity to attenuate the leptin response. We show that mice that lack TCPTP in neuronal cells have enhanced leptin sensitivity and are resistant to high-fat-diet-induced weight gain and the development of leptin resistance. Also, intracerebroventricular administration of a TCPTP inhibitor enhances leptin signaling and responses in mice. Moreover, the combined deletion of TCPTP and PTP1B in neuronal cells has additive effects in the prevention of diet-induced obesity. Our results identify TCPTP as a critical negative regulator of hypothalamic leptin signaling and causally link elevated TCPTP to the development of cellular leptin resistance in obesity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Published
2011
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