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

• Published in: Molecular metabolism (Germany) Vol. 3; no. 3; pp. 301 - 312
• Main Authors: Tsou, Ryan C, Rak, Kimberly S, Zimmer, Derek J, Bence, Kendra K
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.06.2014; Elsevier
• Subjects: Endocrinology & Metabolism; Hypothalamus; Leptin; Obesity; Original; Phosphatase; NK2 homeobox 1 protein or thyroid transcription factor-1; db/db; CNTF; Leptin receptor long form; PR domain containing 16; PTPs; GTT; ob/ob; Src homology 2 domain-containing protein tyrosine phosphatase; HFD; ITT; UCP1; Brown adipose tissue; Proopiomelanocortin; WAT; Hypothalamus; Ciliary neurotrophic factor; Phosphatase; Interleukin-6; SHP2; PI3K; Uncoupling protein 1; Janus kinase 2; Leptin receptor-deficient mice; Signal transducer and activator of transcription 3; LepRb; JAK2; Insulin tolerance test; Obesity; Protein tyrosine phosphatases; White adipose tissue; STAT3; Prdm16; Glucose tolerance test; Cre recombinase; IL-6; Nkx2.1; POMC; PTP1B; BAT; hypothalamus–pituitary–adrenal; High-fat diet; Leptin; Cre; leptin-deficient mice; HPA; Protein tyrosine phosphatase 1B; Phosphatidylinositol 3-kinase; CNTF, Ciliary neurotrophic factor; db/db, Leptin receptor-deficient mice; PTP1B, Protein tyrosine phosphatase 1B; Nkx2.1, NK2 homeobox 1 protein or thyroid transcription factor-1; BAT, Brown adipose tissue; GTT, Glucose tolerance test; LepRb, Leptin receptor long form; POMC, Proopiomelanocortin; IL-6, Interleukin-6; Cre, Cre recombinase; WAT, White adipose tissue; HFD, High-fat diet; Prdm16, PR domain containing 16; ITT, Insulin tolerance test; SHP2, Src homology 2 domain-containing protein tyrosine phosphatase; UCP1, Uncoupling protein 1; PTPs, Protein tyrosine phosphatases; STAT3, Signal transducer and activator of transcription 3; JAK2, Janus kinase 2; HPA, hypothalamus–pituitary–adrenal; ob/ob, leptin-deficient mice; PI3K, Phosphatidylinositol 3-kinase
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2014.01.008

Abstract 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.