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Elevated Hypothalamic TCPTP in Obesity Contributes to Cellular Leptin Resistance

Loh, Kim and Fukushima, Atsushi and Zhang, Xinmei and Galic, Sandra and Briggs, Dana and Enriori, Pablo J and Simonds, Stephanie and Wiede, Florian and Reichenbach, Alexander and Hauser, Christine and Sims, Natalie A and Bence, Kendra K and Zhang, Sheng and Zhang, Zhong-Yi and Kahn, Barbara B and Neel, Benjamin G and Andrews, Zane B and Cowley, Michael A and Tiganis, Tony (2011) Elevated Hypothalamic TCPTP in Obesity Contributes to Cellular Leptin Resistance. Cell Metabolism, 14 (5). pp. 684-699. ISSN 1550-4131

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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.

Item Type: Article
Uncontrolled Keywords: ResPubID23494, leptin resistance, protein tyrosine phosphatase 1B, PTP1B, hypothalamic levels, neuronal cells
Subjects: Faculty/School/Research Centre/Department > Institute of Sport, Exercise and Active Living (ISEAL)
FOR Classification > 1101 Medical Biochemistry and Metabolomics
SEO Classification > 970111 Expanding Knowledge in the Medical and Health Sciences
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Depositing User: VUIR
Date Deposited: 24 Aug 2012 05:45
Last Modified: 03 Feb 2015 05:25
URI: http://vuir.vu.edu.au/id/eprint/9095
DOI: 10.1016/j.cmet.2011.09.011
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Citations in Scopus: 28 - View on Scopus

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