PTP1B and TCPTP in CNS Signaling and Energy Balance

Chapter

Abstract

The regulation of energy balance is under tight homeostatic control. Biological mechanisms have evolved over time to ensure adequate nutritional status and appropriate body composition in response to metabolic and environmental stimuli. The central nervous system (CNS) plays an important role in the regulation of body weight and in the control of normal glucose homeostasis. Several key areas of the CNS are involved in energy balance, including the nuclei of the hypothalamus, hindbrain, and limbic (reward) centers of the brain. Within these brain regions critical cellular signaling pathways have been identified that mediate a multitude of metabolic processes, including feeding, body weight gain/loss, energy expenditure, core temperature regulation, peripheral insulin sensitivity, and liver metabolism. Two such pathways are the leptin and insulin signaling pathways. Rapid reversible phosphorylation events within these key CNS signaling pathways are critical to the tight regulation of energy balance control, and disruption of these events can contribute to the pathogenesis of the metabolic syndrome. Protein tyrosine phosphatases, or PTPs, catalyze the dephosphorylation of phosphorylated tyrosyl residues and thus are important regulators of intracellular signaling pathways. In this chapter, the contributions of protein tyrosine phosphatase 1B (PTP1B) and its closest homologue, T cell PTP (TCPTP), to CNS control of energy balance will be highlighted.

Keywords

Obesity Attenuation Tyrosine Anemia Diarrhea 

Abbreviations

AgRP

Agouti-related peptide

ARC

Arcuate nucleus

BAT

Brown adipose tissue

Cga

Glycoprotein hormone alpha-subunit

CNS

Central nervous system

DMH

Dorsomedial hypothalamus

ER

Endoplasmic reticulum

GH

Growth hormone

icv

Intracerebroventricular

IR

Insulin receptor

IRS-1

Insulin receptor substrate-1

JAK-2

Janus-activated kinase 2

LepRb

Leptin receptor

LH

Lateral hypothalamus

MEFs

Mouse embryonic fibroblasts

MTII

Melanotan II

NPY

Neuropeptide Y

NTS

Nucleus of the solitary tract

PI3K

Phosphatidylinositol 3-kinase

POMC

Proopiomelanocortin

PTP1B

Protein tyrosine phosphatase 1B

PVN

Paraventricular nucleus

SHP-2

Src homology phosphatase-2

SOCS3

Suppressor of cytokine signaling 3

TCPTP

T cell PTP

VMH

Ventromedial hypothalamus

VTA

Ventral tegmental area

α-MSH

α-melanocyte-stimulating hormone

Notes

Acknowledgements

T.T. is a National Health and Medical Research Council (NHMRC) of Australia Principal Research Fellow and supported by grants from the NHMRC. K.B. is an Associate Professor at the University of Pennsylvania, School of Veterinary Medicine, and is supported by the National Institutes of Health (NIDDK).

References

  1. 1.
    Dube N, Tremblay ML (2004) Beyond the metabolic function of PTP1B. Cell Cycle 3:550–553PubMedCrossRefGoogle Scholar
  2. 2.
    Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP (1999) Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283:1544–1548PubMedCrossRefGoogle Scholar
  3. 3.
    Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, Moghal N, Lubkin M, Kim YB, Sharpe AH, Stricker-Krongrad A, Shulman GI, Neel BG, Kahn BB (2000) Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol 20:5479–5489PubMedCrossRefGoogle Scholar
  4. 4.
    Kenner KA, Anyanwu E, Olefsky JM, Kusari J (1996) Protein-tyrosine phosphatase 1B is a negative regulator of insulin- and insulin-like growth factor-I-stimulated signaling. J Biol Chem 271:19810–19816PubMedCrossRefGoogle Scholar
  5. 5.
    Ahmad F, Li PM, Meyerovitch J, Goldstein BJ (1995) Osmotic loading of neutralizing antibodies demonstrates a role for protein-tyrosine phosphatase 1B in negative regulation of the insulin action pathway. J Biol Chem 270:20503–20508PubMedCrossRefGoogle Scholar
  6. 6.
    Myers MG, Cowley MA, Munzberg H (2008) Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70:537–556PubMedCrossRefGoogle Scholar
  7. 7.
    Myers MG Jr, Heymsfield SB, Haft C, Kahn BB, Laughlin M, Leibel RL, Tschop MH, Yanovski JA (2012) Challenges and opportunities of defining clinical leptin resistance. Cell Metab 15:150–156PubMedCrossRefGoogle Scholar
  8. 8.
    Marino JS, Xu Y, Hill JW (2011) Central insulin and leptin-mediated autonomic control of glucose homeostasis. Trends Endocrinol Metab 22:275–285PubMedGoogle Scholar
  9. 9.
    Xu Y, Elmquist JK, Fukuda M (2011) Central nervous control of energy and glucose balance: focus on the central melanocortin system. Ann N Y Acad Sci 1243:1–14PubMedCrossRefGoogle Scholar
  10. 10.
    Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG (1996) Identification of targets of leptin action in rat hypothalamus. J Clin Invest 98:1101–1106PubMedCrossRefGoogle Scholar
  11. 11.
    Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P, Baskin DG (1997) Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46:2119–2123PubMedCrossRefGoogle Scholar
  12. 12.
    Mizuno TM, Kleopoulos SP, Bergen HT, Roberts JL, Priest CA, Mobbs CV (1998) Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and [corrected] in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 47:294–297PubMedCrossRefGoogle Scholar
  13. 13.
    Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, Flier JS, Saper CB, Elmquist JK (1999) Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23:775–786PubMedCrossRefGoogle Scholar
  14. 14.
    Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD, Low MJ (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411:480–484PubMedCrossRefGoogle Scholar
  15. 15.
    Hayes MR, Skibicka KP, Leichner TM, Guarnieri DJ, DiLeone RJ, Bence KK, Grill HJ (2010) Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metab 11:77–83PubMedCrossRefGoogle Scholar
  16. 16.
    Scott MM, Williams KW, Rossi J, Lee CE, Elmquist JK (2011) Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice. J Clin Invest 121:2413–2421PubMedCrossRefGoogle Scholar
  17. 17.
    Figlewicz DP, MacDonald Naleid A, Sipols AJ (2007) Modulation of food reward by adiposity signals. Physiol Behav 91:473–478PubMedCrossRefGoogle Scholar
  18. 18.
    Fulton S, Woodside B, Shizgal P (2000) Modulation of brain reward circuitry by leptin. Science 287:125–128PubMedCrossRefGoogle Scholar
  19. 19.
    Fulton S, Pissios P, Manchon RP, Stiles L, Frank L, Pothos EN, Maratos-Flier E, Flier JS (2006) Leptin regulation of the mesoaccumbens dopamine pathway. Neuron 51:811–822PubMedCrossRefGoogle Scholar
  20. 20.
    Hommel JD, Trinko R, Sears RM, Georgescu D, Liu ZW, Gao XB, Thurmon JJ, Marinelli M, DiLeone RJ (2006) Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51:801–810PubMedCrossRefGoogle Scholar
  21. 21.
    Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632–635PubMedCrossRefGoogle Scholar
  22. 22.
    Kloek C, Haq AK, Dunn SL, Lavery HJ, Banks AS, Myers MG Jr (2002) Regulation of Jak kinases by intracellular leptin receptor sequences. J Biol Chem 277:41547–41555PubMedCrossRefGoogle Scholar
  23. 23.
    Villanueva EC, Myers MG Jr (2008) Leptin receptor signaling and the regulation of mammalian physiology. Int J Obes (Lond) 32(Suppl 7):S8–S12CrossRefGoogle Scholar
  24. 24.
    Hill JW, Williams KW, Ye C, Luo J, Balthasar N, Coppari R, Cowley MA, Cantley LC, Lowell BB, Elmquist JK (2008) Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J Clin Invest 118:1796–1805PubMedCrossRefGoogle Scholar
  25. 25.
    Xu Y, Hill JW, Fukuda M, Gautron L, Sohn JW, Kim KW, Lee CE, Choi MJ, Lauzon DA, Dhillon H, Lowell BB, Zigman JM, Zhao JJ, Elmquist JK (2010) PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis. Cell Metab 12:88–95PubMedCrossRefGoogle Scholar
  26. 26.
    Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers MG Jr, Seeley RJ, Schwartz MW (2003) Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52:227–231PubMedCrossRefGoogle Scholar
  27. 27.
    Dagon Y, Hur E, Zheng B, Wellenstein K, Cantley LC, Kahn BB (2012) p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin’s effect on food intake. Cell Metab 16:104–112PubMedCrossRefGoogle Scholar
  28. 28.
    Salmeen A, Andersen JN, Myers MP, Tonks NK, Barford D (2000) Molecular basis for recognition and dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. Mol Cell 6:1401–1412PubMedCrossRefGoogle Scholar
  29. 29.
    Myers MP, Andersen JN, Cheng A, Tremblay ML, Horvath CM, Parisien JP, Salmeen A, Barford D, Tonks NK (2001) TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J Biol Chem 276:47771–47774PubMedCrossRefGoogle Scholar
  30. 30.
    Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, Kim YB, Elmquist JK, Tartaglia LA, Kahn BB, Neel BG (2002) PTP1B regulates leptin signal transduction in vivo. Dev Cell 2:489–495PubMedCrossRefGoogle Scholar
  31. 31.
    Cheng A, Uetani N, Simoncic PD, Chaubey VP, Lee-Loy A, McGlade CJ, Kennedy BP, Tremblay ML (2002) Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev Cell 2:497–503PubMedCrossRefGoogle Scholar
  32. 32.
    Lund IK, Hansen JA, Andersen HS, Moller NP, Billestrup N (2005) Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling. J Mol Endocrinol 34:339–351PubMedCrossRefGoogle Scholar
  33. 33.
    Kaszubska W, Falls HD, Schaefer VG, Haasch D, Frost L, Hessler P, Kroeger PE, White DW, Jirousek MR, Trevillyan JM (2002) Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line. Mol Cell Endocrinol 195:109–118PubMedCrossRefGoogle Scholar
  34. 34.
    Guan KL, Haun RS, Watson SJ, Geahlen RL, Dixon JE (1990) Cloning and expression of a protein-tyrosine-phosphatase. Proc Natl Acad Sci U S A 87:1501–1505PubMedCrossRefGoogle Scholar
  35. 35.
    Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, Kahn BB (2006) Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med 12:917–924PubMedCrossRefGoogle Scholar
  36. 36.
    Delibegovic M, Bence KK, Mody N, Hong EG, Ko HJ, Kim JK, Kahn BB, Neel BG (2007) Improved glucose homeostasis in mice with muscle-specific deletion of protein-tyrosine phosphatase 1B. Mol Cell Biol 27:7727–7734PubMedCrossRefGoogle Scholar
  37. 37.
    Delibegovic M, Zimmer D, Kauffman C, Rak K, Hong EG, Cho YR, Kim JK, Kahn BB, Neel BG, Bence KK (2009) Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced ER stress. Diabetes 58:590–599PubMedCrossRefGoogle Scholar
  38. 38.
    Agouni A, Mody N, Owen C, Czopek A, Zimmer D, Bentires-Alj M, Bence KK, Delibegovic M (2011) Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress. Biochem J 438:369–378PubMedCrossRefGoogle Scholar
  39. 39.
    Owen C, Czopek A, Agouni A, Grant L, Judson R, Lees EK, McIlroy GD, Goransson O, Welch A, Bence KK, Kahn BB, Neel BG, Mody N, Delibegovic M (2012) Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis. PLoS One 7:e32700PubMedCrossRefGoogle Scholar
  40. 40.
    Morrison CD, White CL, Wang Z, Lee SY, Lawrence DS, Cefalu WT, Zhang ZY, Gettys TW (2007) Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age. Endocrinology 148:433–440PubMedCrossRefGoogle Scholar
  41. 41.
    Picardi PK, Calegari VC, Prada Pde O, Moraes JC, Araujo E, Marcondes MC, Ueno M, Carvalheira JB, Velloso LA, Saad MJ (2008) Reduction of hypothalamic protein tyrosine phosphatase improves insulin and leptin resistance in diet-induced obese rats. Endocrinology 149:3870–3880PubMedCrossRefGoogle Scholar
  42. 42.
    Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, Kenny CD, McGovern RA, Chua SC Jr, Elmquist JK, Lowell BB (2004) Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42:983–991PubMedCrossRefGoogle Scholar
  43. 43.
    Huo L, Gamber K, Greeley S, Silva J, Huntoon N, Leng XH, Bjorbaek C (2009) Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab 9:537–547PubMedCrossRefGoogle Scholar
  44. 44.
    Banno R, Zimmer D, De Jonghe BC, Atienza M, Rak K, Yang W, Bence KK (2010) PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. J Clin Invest 120:720–734PubMedCrossRefGoogle Scholar
  45. 45.
    De Jonghe BC, Hayes MR, Banno R, Skibicka KPPD, Zimmer DJ, Bowen KAPD, Leichner TM, Alhadeff AL, Kanoski SEPD, Cyr NE, Nillni EA, Grill HJ, Bence KK (2011) Deficiency of PTP1B in POMC neurons leads to alterations in energy balance and homeostatic response to cold exposure. Am J Physiol Endocrinol Metab 300(6):E1002–E1011PubMedCrossRefGoogle Scholar
  46. 46.
    Ellacott KL, Halatchev IG, Cone RD (2006) Characterization of leptin-responsive neurons in the caudal brainstem. Endocrinology 147:3190–3195PubMedCrossRefGoogle Scholar
  47. 47.
    Bronstein DM, Schafer MK, Watson SJ, Akil H (1992) Evidence that beta-endorphin is synthesized in cells in the nucleus tractus solitarius: detection of POMC mRNA. Brain Res 587:269–275PubMedCrossRefGoogle Scholar
  48. 48.
    Palkovits M, Eskay RL (1987) Distribution and possible origin of beta-endorphin and ACTH in discrete brainstem nuclei of rats. Neuropeptides 9:123–137PubMedCrossRefGoogle Scholar
  49. 49.
    De Jonghe BC, Hayes MR, Kanoski SE, Zimmer DJ, Grill HJ, Bence KK (2012) Food intake reductions and increases in energetic responses by hindbrain leptin and melanotan II are enhanced in mice with POMC-specific PTP1B deficiency. Am J Physiol Endocrinol Metab 303(5):E644–E651PubMedCrossRefGoogle Scholar
  50. 50.
    Ali MI, Ketsawatsomkron P, Belin de Chantemele EJ, Mintz JD, Muta K, Salet C, Black SM, Tremblay ML, Fulton DJ, Marrero MB, Stepp DW (2009) Deletion of protein tyrosine phosphatase 1b improves peripheral insulin resistance and vascular function in obese, leptin-resistant mice via reduced oxidant tone. Circ Res 105:1013–1022PubMedCrossRefGoogle Scholar
  51. 51.
    Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671PubMedGoogle Scholar
  52. 52.
    Porte D Jr, Baskin DG, Schwartz MW (2005) Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes 54:1264–1276PubMedCrossRefGoogle Scholar
  53. 53.
    Galic S, Hauser C, Kahn BB, Haj FG, Neel BG, Tonks NK, Tiganis T (2005) Coordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTP. Mol Cell Biol 25:819–829PubMedCrossRefGoogle Scholar
  54. 54.
    Goldstein BJ, Bittner-Kowalczyk A, White MF, Harbeck M (2000) Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein. J Biol Chem 275:4283–4289PubMedCrossRefGoogle Scholar
  55. 55.
    Revuelta-Cervantes J, Mayoral R, Miranda S, Gonzalez-Rodriguez A, Fernandez M, Martin-Sanz P, Valverde AM (2011) Protein tyrosine phosphatase 1B (PTP1B) deficiency accelerates hepatic regeneration in mice. Am J Pathol 178:1591–1604PubMedCrossRefGoogle Scholar
  56. 56.
    Chang Y (2011) A central role of PTP1B in hyperinsulinemia-enhanced IL-6 signaling in dedifferentiated vascular smooth muscle cells. J Diabet Metabol 2:118CrossRefGoogle Scholar
  57. 57.
    Wallenius K, Wallenius V, Sunter D, Dickson SL, Jansson JO (2002) Intracerebroventricular interleukin-6 treatment decreases body fat in rats. Biochem Biophys Res Commun 293:560–565PubMedCrossRefGoogle Scholar
  58. 58.
    Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO (2002) Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8:75–79PubMedCrossRefGoogle Scholar
  59. 59.
    Cool DE, Tonks NK, Charbonneau H, Walsh KA, Fischer EH, Krebs EG (1989) cDNA isolated from a human T-cell library encodes a member of the protein-tyrosine-phosphatse family. Proc Natl Acad Sci U S A 86:5257–5261PubMedCrossRefGoogle Scholar
  60. 60.
    You-Ten KE, Muise ES, Itie A, Michaliszyn E, Wagner J, Jothy S, Lapp WS, Tremblay ML (1997) Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. J Exp Med 186:683–693PubMedCrossRefGoogle Scholar
  61. 61.
    Wiede F, Shields BJ, Chew SH, Kyparissoudis K, van Vliet C, Galic S, Tremblay ML, Russell SM, Godfrey DI, Tiganis T (2011) T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J Clin Invest 121:4758–4774PubMedCrossRefGoogle Scholar
  62. 62.
    Tiganis T, Bennett AM (2007) Protein tyrosine phosphatase function: the substrate perspective. Biochem J 402:1–15PubMedCrossRefGoogle Scholar
  63. 63.
    Tiganis T (2013) PTP1B and TCPTP—nonredundant phosphatases in insulin signaling and glucose homeostasis. FEBS J 280(2):445–458PubMedCrossRefGoogle Scholar
  64. 64.
    Mosinger B Jr, Tillmann U, Westphal H, Tremblay ML (1992) Cloning and characterization of a mouse cDNA encoding a cytoplasmic protein-tyrosine-phosphatase. Proc Natl Acad Sci U S A 89:499–503PubMedCrossRefGoogle Scholar
  65. 65.
    Tillmann U, Wagner J, Boerboom D, Westphal H, Tremblay ML (1994) Nuclear localization and cell cycle regulation of a murine protein tyrosine phosphatase. Mol Cell Biol 14:3030–3040PubMedGoogle Scholar
  66. 66.
    Lorenzen JA, Dadabay CY, Fischer EH (1995) COOH-Terminal sequence motifs target the T-cell protein tyrosine phosphatase to the ER and nucleus. J Cell Biol 131:631–643PubMedCrossRefGoogle Scholar
  67. 67.
    Tiganis T, Flint AJ, Adam SA, Tonks NK (1997) Association of the T-cell protein tyrosine phosphatase with nuclear import factor p97. J Biol Chem 272:21548–21557PubMedCrossRefGoogle Scholar
  68. 68.
    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 (2011) Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metab 14:684–699PubMedCrossRefGoogle Scholar
  69. 69.
    Haj FG, Verveer PJ, Squire A, Neel BG, Bastiaens PI (2002) Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum. Science 295:1708–1711PubMedCrossRefGoogle Scholar
  70. 70.
    Nievergall E, Janes PW, Stegmayer C, Vail ME, Haj FG, Teng SW, Neel BG, Bastiaens PI, Lackmann M (2010) PTP1B regulates Eph receptor function and trafficking. J Cell Biol 191:1189–1203PubMedCrossRefGoogle Scholar
  71. 71.
    Eden ER, White IJ, Tsapara A, Futter CE (2010) Membrane contacts between endosomes and ER provide sites for PTP1B-epidermal growth factor receptor interaction. Nat Cell Biol 12:267–272PubMedGoogle Scholar
  72. 72.
    Haj FG, Sabet O, Kinkhabwala A, Wimmer-Kleikamp S, Roukos V, Han HM, Grabenbauer M, Bierbaum M, Antony C, Neel BG, Bastiaens PI (2012) Regulation of signaling at regions of cell-cell contact by endoplasmic reticulum-bound protein-tyrosine phosphatase 1B. PLoS One 7:e36633PubMedCrossRefGoogle Scholar
  73. 73.
    Monteleone MC, Gonzalez Wusener AE, Burdisso JE, Conde C, Caceres A, Arregui CO (2012) ER-bound protein tyrosine phosphatase PTP1B interacts with Src at the plasma membrane/substrate interface. PLoS One 7:e38948PubMedCrossRefGoogle Scholar
  74. 74.
    Tiganis T, Kemp BE, Tonks NK (1999) The protein tyrosine phosphatase TCPTP regulates epidermal growth factor receptor-mediated and phosphatidylinositol 3-kinase-dependent signalling. J Biol Chem 274:27768–27775PubMedCrossRefGoogle Scholar
  75. 75.
    Tiganis T, Bennett AM, Ravichandran KS, Tonks NK (1998) Epidermal growth factor receptor and the adaptor protein p52Shc are specific substrates of T-cell protein tyrosine phosphatase. Mol Cell Biol 18:1622–1634PubMedGoogle Scholar
  76. 76.
    Lam MH, Michell BJ, Fodero-Tavoletti MT, Kemp BE, Tonks NK, Tiganis T (2001) Cellular stress regulates the nucleocytoplasmic distribution of the protein tyrosine phosphatase TCPTP. J Biol Chem 276:37700–37707PubMedCrossRefGoogle Scholar
  77. 77.
    Galic S, Klingler-Hoffmann M, Fodero-Tavoletti MT, Puryer MA, Meng TC, Tonks NK, Tiganis T (2003) Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP. Mol Cell Biol 23:2096–2108PubMedCrossRefGoogle Scholar
  78. 78.
    van Vliet C, Bukczynska PE, Puryer MA, Sadek CM, Shields BJ, Tremblay ML, Tiganis T (2005) Selective regulation of tumor necrosis factor-induced Erk signaling by Src family kinases and the T cell protein tyrosine phosphatase. Nat Immunol 6:253–260PubMedCrossRefGoogle Scholar
  79. 79.
    Fukushima A, Loh K, Galic S, Fam B, Shields B, Wiede F, Tremblay ML, Watt MJ, Andrikopoulos S, Tiganis T (2010) T-cell protein tyrosine phosphatase attenuates STAT3 and insulin signaling in the liver to regulate gluconeogenesis. Diabetes 59:1906–1914PubMedCrossRefGoogle Scholar
  80. 80.
    Shields BJ, Hauser C, Bukczynska PE, Court NW, Tiganis T (2008) DNA replication stalling attenuates tyrosine kinase signaling to suppress S phase progression. Cancer Cell 14:166–179PubMedCrossRefGoogle Scholar
  81. 81.
    Simoncic PD, Lee-Loy A, Barber DL, Tremblay ML, McGlade CJ (2002) The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3. Curr Biol 12: 446–453PubMedCrossRefGoogle Scholar
  82. 82.
    Aoki N, Matsuda T (2002) A nuclear protein tyrosine phosphatase TC-PTP is a potential negative regulator of the PRL-mediated signaling pathway: dephosphorylation and deactivation of signal transducer and activator of transcription 5a and 5b by TC-PTP in nucleus. Mol Endocrinol 16:58–69PubMedCrossRefGoogle Scholar
  83. 83.
    Yamamoto T, Sekine Y, Kashima K, Kubota A, Sato N, Aoki N, Matsuda T (2002) The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation. Biochem Biophys Res Commun 297:811–817PubMedCrossRefGoogle Scholar
  84. 84.
    ten Hoeve J, Ibarra-Sanchez MJ, Fu Y, Zhu W, Tremblay M, David M, Shuai K (2002) Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol Cell Biol 22:5662–5668PubMedCrossRefGoogle Scholar
  85. 85.
    Lu X, Chen J, Sasmono RT, Hsi ED, Sarosiek KA, Tiganis T, Lossos IS (2007) T-cell protein tyrosine phosphatase, distinctively expressed in activated-B-cell-like diffuse large B-cell lymphomas, is the nuclear phosphatase of STAT6. Mol Cell Biol 27:2166–2179PubMedCrossRefGoogle Scholar
  86. 86.
    Heinonen KM, Nestel FP, Newell EW, Charette G, Seemayer TA, Tremblay ML, Lapp WS (2004) T Cell Protein Tyrosine Phosphatase deletion results in progressive systemic inflammatory disease. Blood 103(9):3457–3464PubMedCrossRefGoogle Scholar
  87. 87.
    Bourdeau A, Dube N, Heinonen KM, Theberge JF, Doody KM, Tremblay ML (2007) TC-PTP-deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-{gamma}. Blood 109:4220–4228PubMedCrossRefGoogle Scholar
  88. 88.
    Wiede F, Hui Chew S, van Vliet C, Poulton IJ, Kyparissoudis K, Sasmono T, Loh K, Tremblay ML, Godfrey DI, Sims NA, Tiganis T (2012) Strain-dependent differences in bone development, myeloid hyperplasia, morbidity and mortality in Ptpn2-deficient mice. Plos One 7:e36703PubMedCrossRefGoogle Scholar
  89. 89.
    Minami S, Kamegai J, Hasegawa O, Sugihara H, Okada K, Wakabayashi I (1993) Expression of growth hormone receptor gene in rat hypothalamus. J Neuroendocrinol 5:691–696PubMedCrossRefGoogle Scholar
  90. 90.
    Burton KA, Kabigting EB, Clifton DK, Steiner RA (1992) Growth hormone receptor messenger ribonucleic acid distribution in the adult male rat brain and its colocalization in hypothalamic somatostatin neurons. Endocrinology 131:958–963PubMedCrossRefGoogle Scholar
  91. 91.
    Lichanska AM, Waters MJ (2008) How growth hormone controls growth, obesity and sexual dimorphism. Trends Genet 24:41–47PubMedCrossRefGoogle Scholar
  92. 92.
    Bennett E, McGuinness L, Gevers EF, Thomas GB, Robinson IC, Davey HW, Luckman SM (2005) Hypothalamic STAT proteins: regulation of somatostatin neurones by growth hormone via STAT5b. J Neuroendocrinol 17:186–194PubMedCrossRefGoogle Scholar
  93. 93.
    Xue B, Pulinilkunnil T, Murano I, Bence KK, He H, Minokoshi Y, Asakura K, Lee A, Haj F, Furukawa N, Catalano KJ, Delibegovic M, Balschi JA, Cinti S, Neel BG, Kahn BB (2009) Neuronal protein tyrosine phosphatase 1B deficiency results in inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues. Mol Cell Biol 29:4563–4573PubMedCrossRefGoogle Scholar
  94. 94.
    Zhang S, Chen L, Luo Y, Gunawan A, Lawrence DS, Zhang ZY (2009) Acquisition of a potent and selective TC-PTP inhibitor via a stepwise fluorophore-tagged combinatorial synthesis and screening strategy. J Am Chem Soc 131:13072–13079PubMedCrossRefGoogle Scholar
  95. 95.
    El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS (2000) Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 105:1827–1832PubMedCrossRefGoogle Scholar
  96. 96.
    Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV (1996) Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348:159–161PubMedCrossRefGoogle Scholar
  97. 97.
    Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D Jr (1996) Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med 2:589–593PubMedCrossRefGoogle Scholar
  98. 98.
    Horvath TL, Sarman B, Garcia-Caceres C, Enriori PJ, Sotonyi P, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, Pfluger PT, Bronneke HS, Levin BE, Diano S, Cowley MA, Tschop MH (2010) Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci U S A 107:14875–14880PubMedCrossRefGoogle Scholar
  99. 99.
    Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR, Nguyen HT, Fischer JD, Matsen ME, Wisse BE, Morton GJ, Horvath TL, Baskin DG, Tschop MH, Schwartz MW (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122:153–162PubMedCrossRefGoogle Scholar
  100. 100.
    Taghibiglou C, Rashid-Kolvear F, Van Iderstine SC, Le-Tien H, Fantus IG, Lewis GF, Adeli K (2002) Hepatic very low density lipoprotein-ApoB overproduction is associated with attenuated hepatic insulin signaling and overexpression of protein-tyrosine phosphatase 1B in a fructose-fed hamster model of insulin resistance. J Biol Chem 277:793–803PubMedCrossRefGoogle Scholar
  101. 101.
    Lam NT, Lewis JT, Cheung AT, Luk CT, Tse J, Wang J, Bryer-Ash M, Kolls JK, Kieffer TJ (2004) Leptin increases hepatic insulin sensitivity and protein tyrosine phosphatase 1B expression. Mol Endocrinol 18:1333–1345PubMedCrossRefGoogle Scholar
  102. 102.
    Obata T, Maegawa H, Kashiwagi A, Pillay TS, Kikkawa R (1998) High glucose-induced abnormal epidermal growth factor signaling. J Biochem 123:813–820PubMedCrossRefGoogle Scholar
  103. 103.
    Shao J, Gao Y, Yuan Z (1998) [Free fatty acids promoting PTP1B expression in rat skeletal muscle and hepatic cells]. Zhonghua Yi Xue Za Zhi 78:753–755PubMedGoogle Scholar
  104. 104.
    Parvaneh L, Meshkani R, Bakhtiyari S, Mohammadtaghvaie N, Gorganifiruzjaee S, Taheripak G, Golestani A, Foruzandeh M, Larijani B, Taghikhani M (2010) Palmitate and inflammatory state additively induce the expression of PTP1B in muscle cells. Biochem Biophys Res Commun 396:467–471PubMedCrossRefGoogle Scholar
  105. 105.
    Berthou F, Rouch C, Gertler A, Gerozissis K, Taouis M (2011) Chronic central leptin infusion differently modulates brain and liver insulin signaling. Mol Cell Endocrinol 337:89–95PubMedCrossRefGoogle Scholar
  106. 106.
    Zabolotny JM, Kim YB, Welsh LA, Kershaw EE, Neel BG, Kahn BB (2008) Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo. J Biol Chem 283:14230–14241PubMedCrossRefGoogle Scholar
  107. 107.
    Briancon N, McNay DE, Maratos-Flier E, Flier JS (2010) Combined neural inactivation of SOCS-3 and PTP-1B reveal additive, synergistic, and factor-specific roles in the regulation of body energy balance. Diabetes 59:3074–3084PubMedCrossRefGoogle Scholar
  108. 108.
    Vong L, Ye C, Yang Z, Choi B, Chua S Jr, Lowell BB (2011) Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71:142–154PubMedCrossRefGoogle Scholar
  109. 109.
    Haj FG, Zabolotny JM, Kim YB, Kahn BB, Neel BG (2005) Liver specific protein-tyrosine phosphatase 1B (PTP1B) Re-expression alters glucose homeostasis of PTP1B-/-mice. J Biol Chem 280:15038–15046PubMedCrossRefGoogle Scholar
  110. 110.
    Gelling RW, Morton GJ, Morrison CD, Niswender KD, Myers MG Jr, Rhodes CJ, Schwartz MW (2006) Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes. Cell Metab 3:67–73PubMedCrossRefGoogle Scholar
  111. 111.
    Koch L, Wunderlich FT, Seibler J, Konner AC, Hampel B, Irlenbusch S, Brabant G, Kahn CR, Schwenk F, Bruning JC (2008) Central insulin action regulates peripheral glucose and fat metabolism in mice. J Clin Invest 118:2132–2147PubMedGoogle Scholar
  112. 112.
    Plum L, Belgardt BF, Bruning JC (2006) Central insulin action in energy and glucose homeostasis. J Clin Invest 116:1761–1766PubMedCrossRefGoogle Scholar
  113. 113.
    Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller-Wieland D, Kahn CR (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289:2122–2125PubMedCrossRefGoogle Scholar
  114. 114.
    Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L (2002) Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 5:566–572PubMedCrossRefGoogle Scholar
  115. 115.
    Inoue H, Ogawa W, Asakawa A, Okamoto Y, Nishizawa A, Matsumoto M, Teshigawara K, Matsuki Y, Watanabe E, Hiramatsu R, Notohara K, Katayose K, Okamura H, Kahn CR, Noda T, Takeda K, Akira S, Inui A, Kasuga M (2006) Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab 3:267–275PubMedCrossRefGoogle Scholar
  116. 116.
    Scherer T, O’Hare J, Diggs-Andrews K, Schweiger M, Cheng B, Lindtner C, Zielinski E, Vempati P, Su K, Dighe S, Milsom T, Puchowicz M, Scheja L, Zechner R, Fisher SJ, Previs SF, Buettner C (2011) Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab 13:183–194PubMedCrossRefGoogle Scholar
  117. 117.
    Klockener T, Hess S, Belgardt BF, Paeger L, Verhagen LA, Husch A, Sohn JW, Hampel B, Dhillon H, Zigman JM, Lowell BB, Williams KW, Elmquist JK, Horvath TL, Kloppenburg P, Bruning JC (2011) High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat Neurosci 14:911–918PubMedCrossRefGoogle Scholar
  118. 118.
    Schulz C, Paulus K, Johren O, Lehnert H (2012) Intranasal leptin reduces appetite and induces weight loss in rats with diet-induced obesity (DIO). Endocrinology 153:143–153PubMedCrossRefGoogle Scholar
  119. 119.
    Hallschmid M, Higgs S, Thienel M, Ott V, Lehnert H (2012) Postprandial administration of intranasal insulin intensifies satiety and reduces intake of palatable snacks in women. Diabetes 61:782–789PubMedCrossRefGoogle Scholar
  120. 120.
    Benedict C, Brede S, Schioth HB, Lehnert H, Schultes B, Born J, Hallschmid M (2011) Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men. Diabetes 60:114–118PubMedCrossRefGoogle Scholar
  121. 121.
    Jauch-Chara K, Friedrich A, Rezmer M, Melchert UH, G Scholand-Engler H, Hallschmid M, Oltmanns KM (2012) Intranasal insulin suppresses food intake via enhancement of brain energy levels in humans. Diabetes 61:2261–2268PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Animal BiologySchool of Veterinary Medicine, University of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Biochemistry and Molecular BiologyMonash UniversityClaytonAustralia

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