title: Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance.
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.
authors: Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
authors: Kim
authors: K
authors: Loh
authors: Atsushi
authors: A
authors: Fukushima
authors: Xinmei
authors: X
authors: Zhang
authors: Sandra
authors: S
authors: Galic
authors: Dana
authors: D
authors: Briggs
authors: Pablo J
authors: PJ
authors: Enriori
authors: Stephanie
authors: S
authors: Simonds
authors: Florian
authors: F
authors: Wiede
authors: Alexander
authors: A
authors: Reichenbach
authors: Christine
authors: C
authors: Hauser
authors: Natalie A
authors: NA
authors: Sims
authors: Kendra K
authors: KK
authors: Bence
authors: Sheng
authors: S
authors: Zhang
authors: Zhong-Yin
authors: ZY
authors: Zhang
authors: Barbara B
authors: BB
authors: Kahn
authors: Benjamin G
authors: BG
authors: Neel
authors: Zane B
authors: ZB
authors: Andrews
authors: Michael A
authors: MA
authors: Cowley
authors: Tony
authors: T
authors: Tiganis
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001823:Body Composition / Q000187:drug effects; D059305:Diet, High-Fat; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D057967:Infusions, Intraventricular; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D054411:Receptors, Leptin / Q000378:metabolism; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D020738:Leptin; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; C516609:Ptpn1 protein, mouse