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Mol Metab. 2014 Jan 19;3(3):301-12. doi: 10.1016/j.molmet.2014.01.008. eCollection 2014 Jun.

Improved metabolic phenotype of hypothalamic PTP1B-deficiency is dependent upon the leptin receptor.

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Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.


Protein tyrosine phosphatase 1B (PTP1B) is a known regulator of central metabolic signaling, and mice with whole brain-, leptin receptor (LepRb) expressing cell-, or proopiomelanocortin neuron-specific PTP1B-deficiency are lean, leptin hypersensitive, and display improved glucose homeostasis. However, whether the metabolic effects of central PTP1B-deficiency are due to action within the hypothalamus remains unclear. Moreover, whether or not these effects are exclusively due to enhanced leptin signaling is unknown. Here we report that mice with hypothalamic PTP1B-deficiency (Nkx2.1-PTP1B(-/-)) display decreased body weight and adiposity on high-fat diet with no associated improvements in glucose tolerance. Consistent with previous reports, we find that hypothalamic deletion of the LepRb in mice (Nkx2.1-LepRb(-/-)) results in extreme hyperphagia and obesity. Interestingly, deletion of hypothalamic PTP1B and LepRb (Nkx2.1-PTP1B(-/-):LepRb(-/-)) does not rescue the hyperphagia or obesity of Nkx2.1-LepRb(-/-) mice, suggesting that hypothalamic PTP1B contributes to the central control of energy balance through a leptin receptor-dependent pathway.


BAT, Brown adipose tissue; CNTF, Ciliary neurotrophic factor; Cre, Cre recombinase; GTT, Glucose tolerance test; HFD, High-fat diet; HPA, hypothalamus–pituitary–adrenal; Hypothalamus; IL-6, Interleukin-6; ITT, Insulin tolerance test; JAK2, Janus kinase 2; LepRb, Leptin receptor long form; Leptin; Nkx2.1, NK2 homeobox 1 protein or thyroid transcription factor-1; Obesity; PI3K, Phosphatidylinositol 3-kinase; POMC, Proopiomelanocortin; PTP1B, Protein tyrosine phosphatase 1B; PTPs, Protein tyrosine phosphatases; Phosphatase; Prdm16, PR domain containing 16; SHP2, Src homology 2 domain-containing protein tyrosine phosphatase; STAT3, Signal transducer and activator of transcription 3; UCP1, Uncoupling protein 1; WAT, White adipose tissue; db/db, Leptin receptor-deficient mice; ob/ob, leptin-deficient mice

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