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
CELL METABOLISM | CELL PRESS | Published : 2011
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 resp..View full abstract
Awarded by National Institutes of Health
Awarded by NATIONAL CANCER INSTITUTE
Awarded by NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
This work was supported by the National Health and Medical Research Council (NHMRC) of Australia (to T.T., M.A.C., N.A.S., and Z.B.A.), the National Institutes of Health (to Z.-Y.Z. [RO1 CA126937], K.K.B. [RO1-DK082417], B.B.K. [P01 DK56116], and B.G.N. [R37 CA49152]), and funds from the Ontario Ministry of Health and Long-Term Care and the Princess Margaret Hospital Foundation (B.G.N.); Z.B.A. is an ARC Future Fellow, M.A.C. a Pfizer Senior Research Fellow, N.A.S. and T.T. NHMRC Research Fellows, and B.G.N. a Canada Research Chair (Tier I).