Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance

Kim Loh, Atsushi Fukushima, Xinmei Zhang, Sandra Galic, Dana Briggs, Pablo J. Enriori, Stephanie Simonds, Florian Wiede, Alexander Reichenbach, Christine Hauser, Natalie A. Sims, Kendra K. Bence, Sheng Zhang, Zhong-Yin Zhang, Barbara B. Kahn, Benjamin G. Neel, Zane B. Andrews, Michael A. Cowley, Tony Tiganis

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)684-699
Number of pages16
JournalCell Metabolism
Volume14
Issue number5
DOIs
StatePublished - Nov 2 2011

Fingerprint

Leptin
Obesity
Non-Receptor Type 1 Protein Tyrosine Phosphatase
Appetite Depressants
High Fat Diet
Phosphoric Monoester Hydrolases
Weight Gain
Tyrosine
Diet

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Loh, K., Fukushima, A., Zhang, X., Galic, S., Briggs, D., Enriori, P. J., ... Tiganis, T. (2011). Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metabolism, 14(5), 684-699. https://doi.org/10.1016/j.cmet.2011.09.011

Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. / Loh, Kim; Fukushima, Atsushi; Zhang, Xinmei; Galic, Sandra; Briggs, Dana; Enriori, Pablo J.; Simonds, Stephanie; Wiede, Florian; Reichenbach, Alexander; Hauser, Christine; Sims, Natalie A.; Bence, Kendra K.; Zhang, Sheng; Zhang, Zhong-Yin; Kahn, Barbara B.; Neel, Benjamin G.; Andrews, Zane B.; Cowley, Michael A.; Tiganis, Tony.

In: Cell Metabolism, Vol. 14, No. 5, 02.11.2011, p. 684-699.

Research output: Contribution to journalArticle

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, Z-Y, Kahn, BB, Neel, BG, Andrews, ZB, Cowley, MA & Tiganis, T 2011, 'Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance', Cell Metabolism, vol. 14, no. 5, pp. 684-699. https://doi.org/10.1016/j.cmet.2011.09.011
Loh K, Fukushima A, Zhang X, Galic S, Briggs D, Enriori PJ et al. Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metabolism. 2011 Nov 2;14(5):684-699. https://doi.org/10.1016/j.cmet.2011.09.011
Loh, Kim ; Fukushima, Atsushi ; Zhang, Xinmei ; Galic, Sandra ; Briggs, Dana ; Enriori, Pablo J. ; Simonds, Stephanie ; Wiede, Florian ; Reichenbach, Alexander ; Hauser, Christine ; Sims, Natalie A. ; Bence, Kendra K. ; Zhang, Sheng ; Zhang, Zhong-Yin ; Kahn, Barbara B. ; Neel, Benjamin G. ; Andrews, Zane B. ; Cowley, Michael A. ; Tiganis, Tony. / Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. In: Cell Metabolism. 2011 ; Vol. 14, No. 5. pp. 684-699.
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