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Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance.

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.

Pubmed ID: 22000926

Authors

  • 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
  • Tiganis T

Journal

Cell metabolism

Publication Data

November 2, 2011

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P01 DK056116
  • Agency: NIDDK NIH HHS, Id: P01 DK056116-10
  • Agency: NIDDK NIH HHS, Id: P01 DK56116
  • Agency: NIDDK NIH HHS, Id: P30 DK057521
  • Agency: NCI NIH HHS, Id: R01 CA049152
  • Agency: NCI NIH HHS, Id: R01 CA049152-11
  • Agency: NCI NIH HHS, Id: R01 CA126937
  • Agency: NCI NIH HHS, Id: R01 CA126937
  • Agency: NCI NIH HHS, Id: R01 CA126937-01A1
  • Agency: NIDDK NIH HHS, Id: R01 DK082417
  • Agency: NIDDK NIH HHS, Id: R01 DK082417-01A1
  • Agency: NIDDK NIH HHS, Id: R01-DK082417
  • Agency: NCI NIH HHS, Id: R37 CA049152
  • Agency: NCI NIH HHS, Id: R37 CA49152

Mesh Terms

  • Animals
  • Blood Glucose
  • Body Composition
  • Diet, High-Fat
  • Enzyme Inhibitors
  • Female
  • Gene Expression
  • Hypothalamus
  • Infusions, Intraventricular
  • Insulin
  • Leptin
  • Male
  • Mice
  • Mice, Transgenic
  • Neurons
  • Obesity
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Receptors, Leptin
  • Signal Transduction
  • Tissue Culture Techniques