New pharmacological perspectives for the leptin receptor in the treatment of obesity

Frontiers in Endocrinology

Volumn 5, Issue SEP, 2014, Pages

  Roujeau, Clara ^a,b   Jockers, Ralf ^a,b   Dam, Julie ^a,b  

^a INSTITUT COCHIN   (France)

^b UNIVERSITÉ PARIS DESCARTES   (France)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLIN; CELL SURFACE RECEPTOR; CHOLECYSTOKININ; EXENDIN 4; JANUS KINASE 2; LEPTIN; OB 3; PROOPIOMELANOCORTIN; PROTEIN TYROSINE PHOSPHATASE; PROTEIN TYROSINE PHOSPHATASE 1B; STAT3 PROTEIN; SUPPRESSOR OF CYTOKINE SIGNALING 3; SYNTHETIC PEPTIDE; TRODUSQUEMINE; UNCLASSIFIED DRUG;

ALTERNATIVE RNA SPLICING; ARCUATE NUCLEUS; ARTICLE; BIOLUMINESCENCE RESONANCE ENERGY TRANSFER; BLOOD BRAIN BARRIER; CALORIC RESTRICTION; CELL MIGRATION; DRUG ACTIVATION; ENDOPLASMIC RETICULUM STRESS; ENERGY EXPENDITURE; FOOD INTAKE; GENE MUTATION; HUMAN; HYPERLEPTINEMIA; HYPERPHAGIA; INSULIN RESISTANCE; NERVE CELL PLASTICITY; NONHUMAN; OBESITY; PROTEIN TRANSPORT; SIGNAL TRANSDUCTION; TRANS GOLGI NETWORK; X RAY CRYSTALLOGRAPHY;

EID: 84907683590     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2014.00167     Document Type: Article

References (196)

1. Pi-Sunyer X. The medical risks of obesity. Postgrad Med [Internet]. 2009 Nov [cited 2014 Jul 23];121(6):21-33. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2879283&tool=pmcentrez&rendertype=abstract
2. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature [Internet]. 1994 Dec 1 [cited 2014 May 28];372(6505):425-32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7984236
3. Farooqi Sadaf, Jebb Susan LG. Effects of Recombinant Leptin Therapy in a Child with Congenital Leptin Deficiency - NEJM199909163411204 [Internet]. 1999 [cited 2014 Jul 8]. Available from: http://www.nejm.org.gate2.inist.fr/doi/pdf/10.1056/NEJM199909163411204
4. Pelleymounter M.A. et al. Effects of the obese Gene product on body weight regulation in ob/ob mice [Internet]. 1995 [cited 2014 Jul 8]. Available from: http://www.sciencemag.org.gate2.inist.fr/content/269/5223/540.long
5. Ramachandrappa S, Farooqi IS. Genetic approaches to understanding human obesity. J Clin Invest [Internet]. 2011 Jun [cited 2014 Jul 8];121(6):2080-6. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3104766&tool=pmcentrez&rendertype=abstract
6. Blüher S, Shah S, Mantzoros CS. Leptin deficiency: clinical implications and opportunities for therapeutic interventions. J Investig Med [Internet]. 2009 Oct [cited 2014 Jul 8];57(7):784-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19730134
7. Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JM. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A [Internet]. 1997 Aug 5 [cited 2014 Jun 10];94(16):8878-83. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=23177&tool=pmcentrez&rendertype=abstract
8. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature [Internet]. 1998 Oct 22 [cited 2014 Jul 22];395(6704):763-70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9796811
9. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature [Internet]. 1996 Feb 15 [cited 2014 Jul 22];379(6566):632-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8628397
10. Münzberg H, Flier JS, Bjørbaek C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology [Internet]. 2004 Nov [cited 2014 Aug 28];145(11):4880-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15271881
11. Matheny M, Shapiro A, Tümer N, Scarpace PJ. Region-specific diet-induced and leptin-induced cellular leptin resistance includes the ventral tegmental area in rats. Neuropharmacology [Internet]. [cited 2014 Sep 12];60(2-3):480-7. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3014426&tool=pmcentrez&rendertype=abstract
12. Li Z, Ceccarini G, Eisenstein M, Tan K, Friedman JM. Phenotypic effects of an induced mutation of the ObRa isoform of the leptin receptor. Mol Metab [Internet]. Elsevier; 2013 Jan [cited 2014 Jul 8];2(4):364-75. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3854985&tool=pmcentrez&rendertype=abstract
13. Kowalski TJ, Liu SM, Leibel RL, Chua SC. Transgenic complementation of leptin-receptor deficiency. I. Rescue of the obesity/diabetes phenotype of LEPR-null mice expressing a LEPR-B transgene. Diabetes [Internet]. 2001 Feb [cited 2014 Sep 12];50(2):425-35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11272157
14. McMinn JE, Liu S-M, Liu H, Dragatsis I, Dietrich P, Ludwig T, et al. Neuronal deletion of Lepr elicits diabesity in mice without affecting cold tolerance or fertility. Am J Physiol Endocrinol Metab [Internet]. 2005 Sep [cited 2014 Sep 12];289(3):E403-Available from: http://www.ncbi.nlm.nih.gov/pubmed/15870101
15. Ring LE, Zeltser LM. Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels. J Clin Invest [Internet]. 2010 Aug [cited 2014 Sep 12];120(8):2931-41. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2912188&tool=pmcentrez&rendertype=abstract
16. Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AWK, Wang Y, et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature [Internet]. 2003 Feb 20 [cited 2014 Jul 26];421(6925):856-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12594516
17. Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW. Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab [Internet]. 2005 Dec [cited 2014 Jul 26];2(6):411-20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16330326
18. Minokoshi Y, Alquier T, Furukawa N, Kim Y-B, Lee A, Xue B, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature [Internet]. 2004 Apr 1 [cited 2014 Jul 15];428(6982):569-74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15058305
19. Gao S, Kinzig KP, Aja S, Scott KA, Keung W, Kelly S, et al. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. Proc Natl Acad Sci U S A [Internet]. 2007 Oct 30 [cited 2014 Jul 26];104(44):17358-63. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2077261&tool=pmcentrez&rendertype=abstract
20. Rahmouni K, Sigmund CD, Haynes WG, Mark AL. Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin. Diabetes [Internet]. 2009 Mar [cited 2014 Jul 26];58(3):536-42. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2646051&tool=pmcentrez&rendertype=abstract
21. Zabeau L, Defeau D, Iserentant H, Vandekerckhove J, Peelman F, Tavernier J. Leptin receptor activation depends on critical cysteine residues in its fibronectin type III subdomains. J Biol Chem [Internet]. 2005 Jun 17 [cited 2014 Jul 8];280(24):22632-40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15840566
22. Fong TM, Huang RR, Tota MR, Mao C, Smith T, Varnerin J, et al. Localization of leptin binding domain in the leptin receptor. Mol Pharmacol [Internet]. 1998 Feb [cited 2014 Jul 26];53(2):234-40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9463481
23. Iserentant H, Peelman F, Defeau D, Vandekerckhove J, Zabeau L, Tavernier J. Mapping of the interface between leptin and the leptin receptor CRH2 domain. J Cell Sci [Internet]. 2005 Jun 1 [cited 2014 Jul 8];118(Pt 11):2519-27. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15923664
24. Peelman F, Van Beneden K, Zabeau L, Iserentant H, Ulrichts P, Defeau D, et al. Mapping of the leptin binding sites and design of a leptin antagonist. J Biol Chem [Internet]. 2004 Sep 24 [cited 2014 Jul 26];279(39):41038-46. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15213225
25. Niv-Spector L, Gonen-Berger D, Gourdou I, Biener E, Gussakovsky EE, Benomar Y, et al. Identification of the hydrophobic strand in the A-B loop of leptin as major binding site III: implications for large-scale preparation of potent recombinant human and ovine leptin antagonists. Biochem J [Internet]. 2005 Oct 15 [cited 2014 Jul 16];391(Pt 2):221-30. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1276919&tool=pmcentrez&rendertype=abstract
26. Zabeau L, Verhee A, Catteeuw D, Faes L, Seeuws S, Decruy T, et al. Selection of non-competitive leptin antagonists using a random nanobody-based approach. Biochem J [Internet]. 2012 Jan 1 [cited 2014 Jul 24];441(1):425-34. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21851341
27. Shpilman M, Niv-Spector L, Katz M, Varol C, Solomon G, Ayalon-Soffer M, et al. Development and characterization of high affinity leptins and leptin antagonists. J Biol Chem [Internet]. 2011 Feb 11 [cited 2014 Jul 18];286(6):4429-42. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3039357&tool=pmcentrez&rendertype=abstract
28. Zabeau L, Defeau D, Van der Heyden J, Iserentant H, Vandekerckhove J, Tavernier J. Functional analysis of leptin receptor activation using a Janus kinase/signal transducer and activator of transcription complementation assay. Mol Endocrinol [Internet]. 2004 Jan [cited 2014 Jul 8];18(1):150-61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14525952
29. Peelman F, Iserentant H, De Smet A-S, Vandekerckhove J, Zabeau L, Tavernier J. Mapping of binding site III in the leptin receptor and modeling of a hexameric leptin.leptin receptor complex. J Biol Chem [Internet]. 2006 Jun 2 [cited 2014 Jul 26];281(22):15496-504. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16540470
30. Mancour L V, Daghestani HN, Dutta S, Westfield GH, Schilling J, Oleskie AN, et al. Ligand-induced architecture of the leptin receptor signaling complex. Mol Cell [Internet]. Elsevier Inc.; 2012 Nov 30 [cited 2014 Jul 8];48(4):655-61. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3513567&tool=pmcentrez&rendertype=abstract
31. Moharana K, Zabeau L, Peelman F, Ringler P, Stahlberg H, Tavernier J, et al. Structural and Mechanistic Paradigm of Leptin Receptor Activation Revealed by Complexes with Wild-Type and Antagonist Leptins. Structure [Internet]. Elsevier Ltd; 2014 May [cited 2014 Jun 2];1-12. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0969212614001361
32. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell [Internet]. 1996 Feb 9 [cited 2014 Jul 26];84(3):491-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8608603
33. Lee G, Li C, Montez J, Halaas J, Darvishzadeh J, Friedman JM. Leptin receptor mutations in 129 db3J/db3J mice and NIH facp/facp rats. Mamm Genome [Internet]. 1997 Jun [cited 2014 Jul 26];8(6):445-7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9166593
34. Phillips MS, Liu Q, Hammond HA, Dugan V, Hey PJ, Caskey CJ, et al. Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet [Internet]. 1996 May [cited 2014 Jul 26];13(1):18-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8673096
35. Takaya K, Ogawa Y, Hiraoka J, Hosoda K, Yamori Y, Nakao K, et al. Nonsense mutation of leptin receptor in the obese spontaneously hypertensive Koletsky rat. Nat Genet [Internet]. 1996 Oct [cited 2014 Jul 26];14(2):130-1. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8841178
36. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature [Internet]. 1997 Jun 26 [cited 2014 Jul 24];387(6636):903-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9202122
37. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet [Internet]. 1998 Mar [cited 2014 Jul 26];18(3):213-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9500540
38. Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature [Internet]. 1998 Mar 26 [cited 2014 Jul 26];392(6674):398-401. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9537324
39. Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med [Internet]. 2007 Jan 18 [cited 2014 Jul 26];356(3):237-47. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2670197&tool=pmcentrez&rendertype=abstract
40. Kimber W, Peelman F, Prieur X, Wangensteen T, O'Rahilly S, Tavernier J, et al. Functional characterization of naturally occurring pathogenic mutations in the human leptin receptor. Endocrinology [Internet]. 2008 Dec [cited 2014 Jul 26];149(12):6043-52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18703626
41. Vasselli JR, Scarpace PJ, Harris RBS, Banks WA. Dietary components in the development of leptin resistance. Adv Nutr [Internet]. 2013 Mar [cited 2014 Aug 6];4(2):164-75. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3649097&tool=pmcentrez&rendertype=abstract
42. Vasselli JR. The role of dietary components in leptin resistance. Adv Nutr [Internet]. 2012 Jan [cited 2014 Sep 12];3(5):736-Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3648762&tool=pmcentrez&rendertype=abstract
43. Vasselli JR. Fructose-induced leptin resistance: discovery of an unsuspected form of the phenomenon and its significance. Focus on "Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding," by Shapiro et al. Am J Physiol Regul Integr Comp Physiol [Internet]. 2008 Nov [cited 2014 Sep 12];295(5):R1365-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18784330
44. Wang J, Obici S, Morgan K, Barzilai N, Feng Z, Rossetti L. Overfeeding rapidly induces leptin and insulin resistance. Diabetes [Internet]. 2001 Dec [cited 2014 Sep 12];50(12):2786-91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11723062
45. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet [Internet]. 1996 Jul 20;348(9021):159-61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8684156
46. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med [Internet]. 1996 May [cited 2014 Jul 14];2(5):589-93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8616722
47. Van Heek M, Compton DS, France CF, Tedesco RP, Fawzi a B, Graziano MP, et al. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest [Internet]. 1997 Feb 1;99(3):385-90. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=507810&tool=pmcentrez&rendertype=abstract
48. Banks W a, DiPalma CR, Farrell CL. Impaired transport of leptin across the blood-brain barrier in obesity. Peptides [Internet]. 1999 Nov;20(11):1341-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10612449
49. Burguera B, Couce ME, Curran GL, Jensen MD, Lloyd R V, Cleary MP, et al. Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats. Diabetes [Internet]. 2000 Jul [cited 2014 Jul 15];49(7):1219-23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10909981
50. El-Haschimi K, Pierroz DD, Hileman SM, Bjørbaek C, Flier JS. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest [Internet]. 2000 Jun;105(12):1827-32. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=378516&tool=pmcentrez&rendertype=abstract
51. Horvath TL. Synaptic plasticity in energy balance regulation. Obesity (Silver Spring) [Internet]. 2006 Aug [cited 2014 Jul 26];14 Suppl 5:228S-233S. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17021372
52. Grillo CA, Piroli GG, Junor L, Wilson SP, Mott DD, Wilson MA, et al. Obesity/hyperleptinemic phenotype impairs structural and functional plasticity in the rat hippocampus. Physiol Behav [Internet]. 2011 Nov 30 [cited 2014 Jul 26];105(1):138-44. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3129487&tool=pmcentrez&rendertype=abstract
53. Benani A, Hryhorczuk C, Gouazé A, Fioramonti X, Brenachot X, Guissard C, et al. Food intake adaptation to dietary fat involves PSA-dependent rewiring of the arcuate melanocortin system in mice. J Neurosci [Internet]. 2012 Aug 29 [cited 2014 Jul 26];32(35):11970-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22933782
54. Bjørbaek C, El-Haschimi K, Frantz JD, Flier JS. The role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem [Internet]. 1999 Oct 15 [cited 2014 Jul 22];274(42):30059-65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10514492
55. Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, et al. PTP1B regulates leptin signal transduction in vivo. Dev Cell [Internet]. 2002 Apr [cited 2014 Jul 22];2(4):489-95. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11970898
56. Björnholm M, Münzberg H, Leshan RL, Villanueva EC, Bates SH, Louis GW, et al. Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. J Clin Invest [Internet]. 2007 May [cited 2014 Jul 22];117(5):1354-60. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1838925&tool=pmcentrez&rendertype=abstract
57. Reed AS, Unger EK, Olofsson LE, Piper ML, Myers MG, Xu AW. Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis. Diabetes [Internet]. 2010 Apr [cited 2014 Jul 22];59(4):894-906. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2844837&tool=pmcentrez&rendertype=abstract
58. Cho H. Protein tyrosine phosphatase 1B (PTP1B) and obesity. [Internet]. 1st ed. Vitamins and hormones. Elsevier Inc.; 2013 [cited 2014 Jul 8]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23374726
59. Knight Z a, Hannan KS, Greenberg ML, Friedman JM. Hyperleptinemia is required for the development of leptin resistance. PLoS One [Internet]. 2010 Jan [cited 2014 Jun 23];5(6):e11376. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2894068&tool=pmcentrez&rendertype=abstract
60. Fernández-Galaz C, Fernández-Agulló T, Campoy F, Arribas C, Gallardo N, Andrés A, et al. Decreased leptin uptake in hypothalamic nuclei with ageing in Wistar rats. J Endocrinol [Internet]. 2001 Oct [cited 2014 Jul 26];171(1):23-32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11572787
61. Wilsey J, Scarpace PJ. Caloric restriction reverses the deficits in leptin receptor protein and leptin signaling capacity associated with diet-induced obesity: role of leptin in the regulation of hypothalamic long-form leptin receptor expression. J Endocrinol [Internet]. 2004 May [cited 2014 Jul 26];181(2):297-306. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15128278
62. Zhang Y, Scarpace PJ. The role of leptin in leptin resistance and obesity. Physiol Behav [Internet]. 2006 Jul 30 [cited 2014 May 31];88(3):249-56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16782141
63. Ozcan U, Cao Q, Yilmaz E, Lee A-H, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science [Internet]. 2004 Oct 15 [cited 2014 Jul 18];306(5695):457-61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15486293
64. Hosoi T, Sasaki M, Miyahara T, Hashimoto C, Matsuo S, Yoshii M, et al. Endoplasmic reticulum stress induces leptin resistance. Mol Pharmacol [Internet]. 2008 Dec [cited 2014 Jul 26];74(6):1610-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18755873
65. Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab [Internet]. Elsevier Inc.; 2009 Jan 7 [cited 2014 Jun 24];9(1):35-51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19117545
66. Won JC, Jang P-G, Namkoong C, Koh EH, Kim SK, Park J-Y, et al. Central administration of an endoplasmic reticulum stress inducer inhibits the anorexigenic effects of leptin and insulin. Obesity (Silver Spring) [Internet]. 2009 Oct [cited 2014 Jul 26];17(10):1861-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19543218
67. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med [Internet]. 1999 Sep 16 [cited 2014 Jul 26];341(12):879-84. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10486419
68. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest [Internet]. 2002 Oct [cited 2014 Jul 26];110(8):1093-103. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=150795&tool=pmcentrez&rendertype=abstract
69. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med [Internet]. 2002 Feb 21 [cited 2014 Jul 14];346(8):570-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11856796
70. Javor ED, Ghany MG, Cochran EK, Oral EA, DePaoli AM, Premkumar A, et al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology [Internet]. 2005 Apr [cited 2014 Jul 26];41(4):753-60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15791619
71. Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med [Internet]. 2004 Sep 2 [cited 2014 Jul 26];351(10):987-97. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15342807
72. Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A [Internet]. 2011 Apr 19 [cited 2014 Jul 26];108(16):6585-90. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3080974&tool=pmcentrez&rendertype=abstract
73. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA [Internet]. 1999 Oct 27 [cited 2014 Jul 26];282(16):1568-75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10546697
74. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med [Internet]. 1995 Mar 9 [cited 2014 Jul 26];332(10):621-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7632212
75. Lecoultre V, Ravussin E, Redman LM. The fall in leptin concentration is a major determinant of the metabolic adaptation induced by caloric restriction independently of the changes in leptin circadian rhythms. J Clin Endocrinol Metab [Internet]. 2011 Sep [cited 2014 Jul 26];96(9):E1512-6. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3167663&tool=pmcentrez&rendertype=abstract
76. Doucet E, St Pierre S, Alméras N, Mauriège P, Richard D, Tremblay A. Changes in energy expenditure and substrate oxidation resulting from weight loss in obese men and women: is there an important contribution of leptin? J Clin Endocrinol Metab [Internet]. 2000 Apr [cited 2014 Jul 26];85(4):1550-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10770196
77. Leibel RL. The role of leptin in the control of body weight. Nutr Rev [Internet]. 2002 Oct [cited 2014 Jul 26];60(10 Pt 2):S15-9; discussion S68-84, 85-7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12403079
78. Rosenbaum M, Sy M, Pavlovich K, Leibel RL, Hirsch J. Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. J Clin Invest [Internet]. 2008 Jul [cited 2014 Jul 17];118(7):2583-91. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2430499&tool=pmcentrez&rendertype=abstract
79. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, et al. Role of leptin in the neuroendocrine response to fasting. Nature [Internet]. 1996 Jul 18 [cited 2014 Jul 26];382(6588):250-2. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8717038
80. Ravussin Y, Gutman R, Diano S, Shanabrough M, Borok E, Sarman B, et al. Effects of chronic weight perturbation on energy homeostasis and brain structure in mice. Am J Physiol Regul Integr Comp Physiol [Internet]. 2011 Jun [cited 2014 Jul 26];300(6):R1352-62. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3119157&tool=pmcentrez&rendertype=abstract
81. Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE, Leibel RL. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol Metab [Internet]. 2002 May [cited 2014 Jul 26];87(5):2391-4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11994393
82. Lutz TA. Amylinergic control of food intake. Physiol Behav [Internet]. 2006 Nov 30 [cited 2014 Jul 9];89(4):465-71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16697020
83. Muff R, Bühlmann N, Fischer JA, Born W. An amylin receptor is revealed following co-transfection of a calcitonin receptor with receptor activity modifying proteins-1 or -3. Endocrinology [Internet]. 1999 Jun [cited 2014 Jul 26];140(6):2924-7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10342886
84. Hay, D., and Poyner DR. Calcitonin receptors [Internet]. IUPHAR Database (IUPHAR-DB). 2013. Available from: http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=11
85. Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci U S A [Internet]. 2008 May 20 [cited 2014 Jul 9];105(20):7257-62. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2438237&tool=pmcentrez&rendertype=abstract
86. Trevaskis JL, Coffey T, Cole R, Lei C, Wittmer C, Walsh B, et al. Amylin-mediated restoration of leptin responsiveness in dietinduced obesity: magnitude and mechanisms. Endocrinology [Internet]. 2008 Nov [cited 2014 Jul 9];149(11):5679-87. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18669592
87. Trevaskis JL, Parkes DG, Roth JD. Insights into amylin-leptin synergy. Trends Endocrinol Metab [Internet]. 2010 Aug [cited 2014 Jul 26];21(8):473-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20413324
88. Trevaskis JL, Lei C, Koda JE, Weyer C, Parkes DG, Roth JD. Interaction of leptin and amylin in the long-term maintenance of weight loss in diet-induced obese rats. Obesity (Silver Spring) [Internet]. 2010 Jan [cited 2014 Jul 20];18(1):21-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19543217
89. Aronne L, Fujioka K, Aroda V, Chen K, Halseth A, Kesty NC, et al. Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study. J Clin Endocrinol Metab [Internet]. 2007 Aug [cited 2014 Jul 9];92(8):2977-83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17504894
90. Ravussin E, Smith SR, Mitchell JA, Shringarpure R, Shan K, Maier H, et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring) [Internet]. 2009 Sep [cited 2014 Jul 9];17(9):1736-43. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2754219&tool=pmcentrez&rendertype=abstract
91. Bhavsar S, Watkins J, Young A. Synergy between amylin and cholecystokinin for inhibition of food intake in mice. Physiol Behav [Internet]. 1998 Jun 15 [cited 2014 Jul 9];64(4):557-61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9761232
92. Trevaskis JL, Turek VF, Griffin PS, Wittmer C, Parkes DG, Roth JD. Multi-hormonal weight loss combinations in diet-induced obese rats: therapeutic potential of cholecystokinin? Physiol Behav [Internet]. 2010 May 11 [cited 2014 Jul 9];100(2):187-Available from: http://www.ncbi.nlm.nih.gov/pubmed/20206194
93. Williams DL, Baskin DG, Schwartz MW. Leptin regulation of the anorexic response to glucagon-like peptide-1 receptor stimulation. Diabetes [Internet]. 2006 Dec [cited 2014 Jul 9];55(12):3387-93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17130484
94. Zhao S, Kanoski SE, Yan J, Grill HJ, Hayes MR. Hindbrain leptin and glucagon-like-peptide-1 receptor signaling interact to suppress food intake in an additive manner. Int J Obes (Lond) [Internet]. 2012 Dec [cited 2014 Jul 9];36(12):1522-8. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3335926&tool=pmcentrez&rendertype=abstract
95. Müller TD, Sullivan LM, Habegger K, Yi C-X, Kabra D, Grant E, et al. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. J Pept Sci [Internet]. 2012 Jun [cited 2014 Jul 9];18(6):383-93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22565812
96. Clemmensen C, Chabenne J, Finan B, Sullivan L, Fischer K, Küchler D, et al. GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet. Diabetes [Internet]. 2014 Apr [cited 2014 Jul 1];63(4):1422-7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24379349
97. Byun K, Gil SY, Namkoong C, Youn B-S, Huang H, Shin M-S, et al. Clusterin/ApoJ enhances central leptin signaling through Lrp2-mediated endocytosis. EMBO Rep [Internet]. 2014 Jul [cited 2014 Jul 26];15(7):801-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24825475
98. Turek VF, Trevaskis JL, Levin BE, Dunn-Meynell AA, Irani B, Gu G, et al. Mechanisms of amylin/leptin synergy in rodent models. Endocrinology [Internet]. 2010 Jan [cited 2014 Jul 9];151(1):143-52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19875640
99. Samson WK, Murphy TC, Robison D, Vargas T, Tau E, Chang JK. A 35 amino acid fragment of leptin inhibits feeding in the rat. Endocrinology [Internet]. 1996 Nov [cited 2014 Jul 8];137(11):5182-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8895397
100. Castaigne J, Demeule M, Boivin D, Lawrence B, Che C. Leptin And Leptin Analog Conjugates And Uses Thereof. France; WO 2010/063123 A1, 2010.
101. Jean-Paul Castaigne, Michel Demeule, Betty Lawrence, Dominique Boivin CC. Leptin and leptin analog conjugates and fusion proteins and uses thereof. France; WO2011153642 A1, 2011.
102. Vadim Kraynov, Anna-Maria A Hays Putnam, Nick Knudsen, Jason Pinkstaff, Heather Myler LS. Modified leptin polypeptides and their uses. WO2009100255 A2, 2009.
103. Patricia Grasso, Daniel W. Lee MCL. Leptin-related peptides. 6777388, 2004.
104. Grasso P, Rozhavskaya-Arena M, Leinung MC, Lee DW. [d-LEU-4]-OB3, a synthetic leptin agonist, improves hyperglycemic control in C57BL/6J ob/ob mice. Regul Pept [Internet]. 2001 Sep [cited 2014 Jul 8];101(1-3):123-9. Available from: http://www.sciencedirect.com/science/article/pii/S0167011501002749
105. Novakovic ZM, Leinung MC, Lee DW, Grasso P. Oral delivery of mouse [d-Leu-4]-OB3, a synthetic peptide amide with leptinlike activity, in male C57BL/6J wild-type and ob/ob mice: effects on energy balance, glycaemic control and serum osteocalcin levels. Diabetes Obes Metab [Internet]. 2010 Jun [cited 2014 Jul 8];12(6):532-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20518808
106. Waldrop MA, Leinung MC, Lee DW, Grasso P. Intranasal delivery of mouse [D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, improves energy balance, glycaemic control, insulin sensitivity and bone formation in leptin-resistant C57BLK/6-m db/db mice. Diabetes Obes Metab [Internet]. 2010 Oct [cited 2014 Jul 8];12(10):871-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20920039
107. Vauthier V, Derviaux C, Douayry N, Roux T, Trinquet E, Jockers R, et al. Design and validation of a homogeneous timeresolved fluorescence-based leptin receptor binding assay. Anal Biochem [Internet]. 2013 May 1 [cited 2014 Jul 8];436(1):1-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23333588
108. SIMPSON, Iain; HIGGINBOTTOM M, CHAPMAN E, HORGAN AV-A. SMALL MOLECULE LEPTIN RECEPTOR MODULATORS. WO/2009/147221, 2009.
109. HIGGINBOTTOM M, SIMPSON I, HORTON J, TYZACK C, HORGAN AV-A. NEW PYRIDINE DERIVATIVES AS LEPTIN RECEPTOR MODULATOR MIMETICS. WO/2009/147216, 2009.
110. Banks AS, Davis SM, Bates SH, Myers MG. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem [Internet]. 2000 May 12 [cited 2014 Jul 21];275(19):14563-72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10799542
111. Bjorbak C, Lavery HJ, Bates SH, Olson RK, Davis SM, Flier JS, et al. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J Biol Chem [Internet]. 2000 Dec 22 [cited 2014 Jul 22];275(51):40649-57. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11018044
112. Myers MP, Andersen JN, Cheng A, Tremblay ML, Horvath CM, Parisien JP, et al. TYK2 and JAK2 are substrates of proteintyrosine phosphatase 1B. J Biol Chem [Internet]. 2001 Dec 21 [cited 2014 Jul 22];276(51):47771-4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11694501
113. Kaszubska W, Falls HD, Schaefer VG, Haasch D, Frost L, Hessler P, et al. Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line. Mol Cell Endocrinol [Internet]. 2002 Sep 30 [cited 2014 Jul 22];195(1- 2):109-18. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12354677
114. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science [Internet]. 1999 Mar 5 [cited 2014 Jul 14];283(5407):1544-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10066179
115. Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, et al. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol [Internet]. 2000 Aug [cited 2014 Jul 14];20(15):5479-89. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=85999&tool=pmcentrez&rendertype=abstract
116. Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med [Internet]. 2006 Aug [cited 2014 Jul 22];12(8):917-24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16845389
117. Banno R, Zimmer D, De Jonghe BC, Atienza M, Rak K, Yang W, et al. PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. J Clin Invest [Internet]. 2010 Mar [cited 2014 Jul 22];120(3):720-34. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2827947&tool=pmcentrez&rendertype=abstract
118. De Jonghe BC, Hayes MR, Banno R, Skibicka KP, Zimmer DJ, Bowen KA, et al. Deficiency of PTP1B in POMC neurons leads to alterations in energy balance and homeostatic response to cold exposure. Am J Physiol Endocrinol Metab [Internet]. 2011 Jun [cited 2014 Jul 14];300(6):E1002-11. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3118594&tool=pmcentrez&rendertype=abstract
119. Bhattarai BR, Kafle B, Hwang J-S, Ham SW, Lee K-H, Park H, et al. Novel thiazolidinedione derivatives with anti-obesity effects: dual action as PTP1B inhibitors and PPAR-? activators. Bioorg Med Chem Lett [Internet]. 2010 Nov 15 [cited 2014 Jul 9];20(22):6758-63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20850970
120. Lantz KA, Hart SGE, Planey SL, Roitman MF, Ruiz-White IA, Wolfe HR, et al. Inhibition of PTP1B by trodusquemine (MSI- 1436) causes fat-specific weight loss in diet-induced obese mice. Obesity (Silver Spring) [Internet]. 2010 Aug [cited 2014 Jul 9];18(8):1516-23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20075852
121. Xu Y, Piston DW, Johnson CH. A bioluminescence resonance energy transfer (BRET) system: application to interacting circadian clock proteins. Proc Natl Acad Sci U S A [Internet]. 1999 Jan 5 [cited 2014 Jul 26];96(1):151-6. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=15108&tool=pmcentrez&rendertype=abstract
122. Pfleger KDG, Eidne KA. Illuminating insights into protein-protein interactions using bioluminescence resonance energy transfer (BRET). Nat Methods [Internet]. 2006 Mar [cited 2014 Jul 26];3(3):165-74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16489332
123. Jockers R. Comment on "The Use of BRET to Study Receptor-Protein Interactions". Front Endocrinol (Lausanne) [Internet]. 2014 Jan [cited 2014 Jul 26];5:3. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3898058&tool=pmcentrez&rendertype=abstract
124. Couturier C, Deprez B. Setting Up a Bioluminescence Resonance Energy Transfer High throughput Screening Assay to Search for Protein/Protein Interaction Inhibitors in Mammalian Cells. Front Endocrinol (Lausanne) [Internet]. 2012 Jan [cited 2014 Jul 22];3:100. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3438444&tool=pmcentrez&rendertype=abstract
125. Corbel C, Wang Q, Bousserouel H, Hamdi A, Zhang B, Lozach O, et al. First BRET-based screening assay performed in budding yeast leads to the discovery of CDK5/p25 interaction inhibitors. Biotechnol J [Internet]. 2011 Jul [cited 2014 Jul 26];6(7):860-70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21681968
126. Diano S, Kalra SP, Horvath TL. Leptin receptor immunoreactivity is associated with the Golgi apparatus of hypothalamic neurons and glial cells. J Neuroendocrinol [Internet]. 1998 Sep [cited 2014 Jul 22];10(9):647-50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9744481
127. De Matteis R, Cinti S. Ultrastructural immunolocalization of leptin receptor in mouse brain. Neuroendocrinology [Internet]. 1998 Dec [cited 2014 Jul 22];68(6):412-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9873205
128. Baskin DG, Schwartz MW, Seeley RJ, Woods SC, Porte D, Breininger JF, et al. Leptin receptor long-form splice-variant protein expression in neuron cell bodies of the brain and co-localization with neuropeptide Y mRNA in the arcuate nucleus. J Histochem Cytochem [Internet]. 1999 Mar [cited 2014 Jul 22];47(3):353-62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10026237
129. Barr VA, Lane K, Taylor SI. Subcellular localization and internalization of the four human leptin receptor isoforms. J Biol Chem [Internet]. 1999 Jul 23 [cited 2014 Jul 22];274(30):21416-24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10409704
130. Lundin A, Rondahl H, Walum E, Wilcke M. Expression and intracellular localization of leptin receptor long isoform-GFP chimera. Biochim Biophys Acta [Internet]. 2000 Dec 11 [cited 2014 Jul 22];1499(1-2):130-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11118645
131. Belouzard S, Delcroix D, Rouillé Y. Low levels of expression of leptin receptor at the cell surface result from constitutive endocytosis and intracellular retention in the biosynthetic pathway. J Biol Chem [Internet]. 2004 Jul 2 [cited 2014 Jun 3];279(27):28499-508. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15123629
132. Belouzard S, Rouillé Y. Ubiquitylation of leptin receptor OB-Ra regulates its clathrin-mediated endocytosis. EMBO J [Internet]. 2006 Mar 8 [cited 2014 Jun 3];25(5):932-42. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1409713&tool=pmcentrez&rendertype=abstract
133. Couturier C, Sarkis C, Séron K, Belouzard S, Chen P, Lenain A, et al. Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity. Proc Natl Acad Sci U S A [Internet]. 2007 Dec 4 [cited 2014 Jul 22];104(49):19476-81. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2148314&tool=pmcentrez&rendertype=abstract
134. Seo S, Guo D-F, Bugge K, Morgan DA, Rahmouni K, Sheffield VC. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet [Internet]. 2009 Apr 1 [cited 2014 Jul 26];18(7):1323-31. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2655773&tool=pmcentrez&rendertype=abstract
135. Haft CR, de la Luz Sierra M, Barr VA, Haft DH, Taylor SI. Identification of a family of sorting nexin molecules and characterization of their association with receptors. Mol Cell Biol [Internet]. 1998 Dec [cited 2014 Jul 26];18(12):7278-87. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=109309&tool=pmcentrez&rendertype=abstract
136. Parks WT, Frank DB, Huff C, Renfrew Haft C, Martin J, Meng X, et al. Sorting nexin 6, a novel SNX, interacts with the transforming growth factor-beta family of receptor serine-threonine kinases. J Biol Chem [Internet]. 2001 Jun 1 [cited 2014 Jul 26];276(22):19332-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11279102
137. De Ceuninck L, Wauman J, Masschaele D, Peelman F, Tavernier J. Reciprocal cross-regulation between RNF41 and USP8 controls cytokine receptor sorting and processing. J Cell Sci [Internet]. 2013 Aug 15;126(Pt 16):3770-81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23750007
138. Séron K, Couturier C, Belouzard S, Bacart J, Monté D, Corset L, et al. Endospanins regulate a postinternalization step of the leptin receptor endocytic pathway. J Biol Chem [Internet]. 2011 May 20 [cited 2014 Jul 22];286(20):17968-81. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3093871&tool=pmcentrez&rendertype=abstract
139. Vauthier V, Swartz TD, Chen P, Roujeau C, Pagnon M, Mallet J, et al. Endospanin 1 silencing in the hypothalamic arcuate nucleus contributes to sustained weight loss of high fat diet obese mice. Gene Ther [Internet]. Nature Publishing Group; 2014 May 1 [cited 2014 May 27];(February):1-7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24784449
140. Kim T-H, Choi D-H, Vauthier V, Dam J, Li X, Nam Y-J, et al. Anti-obesity phenotypic screening looking to increase OBR cell surface expression. J Biomol Screen [Internet]. 2014 Jan [cited 2014 Jul 26];19(1):88-99. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23958651
141. Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM. Leptin enters the brain by a saturable system independent of insulin. Peptides [Internet]. 1996 Jan [cited 2014 Jul 14];17(2):305-11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8801538
142. Hileman SM, Pierroz DD, Masuzaki H, Bjørbaek C, El-Haschimi K, Banks WA, et al. Characterizaton of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity. Endocrinology [Internet]. 2002 Mar [cited 2014 Jul 10];143(3):775-83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11861497
143. Banks WA. Blood-brain barrier and energy balance. Obesity (Silver Spring) [Internet]. 2006 Aug [cited 2014 Jul 10];14 Suppl 5:234S-237S. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17021373
144. Werther GA, Hogg A, Oldfield BJ, McKinley MJ, Figdor R, Allen AM, et al. Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology [Internet]. 1987 Oct [cited 2014 Jul 14];121(4):1562-70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3653038
145. Bjørbaek C, Elmquist JK, Michl P, Ahima RS, van Bueren A, McCall AL, et al. Expression of leptin receptor isoforms in rat brain microvessels. Endocrinology [Internet]. 1998 Aug [cited 2014 Jul 14];139(8):3485-91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9681499
146. Kastin AJ, Pan W, Maness LM, Koletsky RJ, Ernsberger P. Decreased transport of leptin across the blood-brain barrier in rats lacking the short form of the leptin receptor. Peptides [Internet]. 1999 Dec [cited 2014 Jul 15];20(12):1449-53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10698121
147. Hileman SM, Tornøe J, Flier JS, Bjørbaek C. Transcellular transport of leptin by the short leptin receptor isoform ObRa in Madin-Darby Canine Kidney cells. Endocrinology [Internet]. 2000 Jun [cited 2014 Jul 14];141(6):1955-61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10830277
148. Dietrich MO, Spuch C, Antequera D, Rodal I, de Yébenes JG, Molina JA, et al. Megalin mediates the transport of leptin across the blood-CSF barrier. Neurobiol Aging [Internet]. 2008 Jun [cited 2014 Jul 26];29(6):902-12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17324488
149. Oh-I S, Shimizu H, Sato T, Uehara Y, Okada S, Mori M. Molecular mechanisms associated with leptin resistance: n-3 polyunsaturated fatty acids induce alterations in the tight junction of the brain. Cell Metab [Internet]. 2005 May [cited 2014 Jul 8];1(5):331-41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16054080
150. Mitchell SE, Nogueiras R, Morris A, Tovar S, Grant C, Cruickshank M, et al. Leptin receptor gene expression and number in the brain are regulated by leptin level and nutritional status. J Physiol [Internet]. 2009 Jul 15 [cited 2014 Jul 18];587(Pt 14):3573-85. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2742282&tool=pmcentrez&rendertype=abstract
151. Boado RJ, Golden PL, Levin N, Pardridge WM. Up-regulation of blood-brain barrier short-form leptin receptor gene products in rats fed a high fat diet. J Neurochem [Internet]. 1998 Oct [cited 2014 Jul 15];71(4):1761-4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9751212
152. Lynn R. Autoradiographic Localization of Leptin Binding in the Choroid Plexus ofob/obanddb/dbMice. Biochem Biophys Res Commun [Internet]. 1996 Feb 27 [cited 2014 Jul 14];219(3):884-9. Available from: http://www.sciencedirect.com/science/article/pii/S0006291X96903289
153. Abizaid A, Gao Q, Horvath TL. Thoughts for food: brain mechanisms and peripheral energy balance. Neuron [Internet]. 2006 Sep 21 [cited 2014 Jul 14];51(6):691-702. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16982416
154. Balland E, Dam J, Langlet F, Caron E, Steculorum S, Messina A, et al. Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metab [Internet]. 2014 Feb 4 [cited 2014 Jun 2];19(2):293-301. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24506870
155. Yi X, Yuan D, Farr S a, Banks W a, Poon C-D, Kabanov A V. Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity. J Control Release [Internet]. Elsevier B.V.; 2014 Jun 2 [cited 2014 Jun 12]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/24881856
156. Elinav E, Niv-Spector L, Katz M, Price TO, Ali M, Yacobovitz M, et al. Pegylated leptin antagonist is a potent orexigenic agent: preparation and mechanism of activity. Endocrinology [Internet]. 2009 Jul [cited 2014 Jul 18];150(7):3083-91. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2703547&tool=pmcentrez&rendertype=abstract
157. Hukshorn CJ, van Dielen FMH, Buurman WA, Westerterp-Plantenga MS, Campfield LA, Saris WHM. The effect of pegylated recombinant human leptin (PEG-OB) on weight loss and inflammatory status in obese subjects. Int J Obes Relat Metab Disord [Internet]. 2002 Apr [cited 2014 Jul 18];26(4):504-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12075577
158. Kovalszky I, Surmacz E, Scolaro L, Cassone M, Ferla R, Sztodola A, et al. Leptin-based glycopeptide induces weight loss and simultaneously restores fertility in animal models. Diabetes Obes Metab [Internet]. 2010 May [cited 2014 Jul 31];12(5):393-402. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20415687
159. Zhang C, Su Z, Zhao B, Qu Q, Tan Y, Cai L, et al. Tat-modified leptin is more accessible to hypothalamus through brain-blood barrier with a significant inhibition of body-weight gain in high-fat-diet fed mice. Exp Clin Endocrinol Diabetes [Internet]. 2010 Jan [cited 2014 Jul 31];118(1):31-7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19472101
160. Price TO, Farr SA, Yi X, Vinogradov S, Batrakova E, Banks WA, et al. Transport across the blood-brain barrier of pluronic leptin. J Pharmacol Exp Ther [Internet]. 2010 May [cited 2014 Jul 31];333(1):253-63. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2846026&tool=pmcentrez&rendertype=abstract
161. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol [Internet]. 2007 Jul [cited 2014 Jul 15];8(7):519-29. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17565364
162. Lee J, Ozcan U. Unfolded protein response signaling and metabolic diseases. J Biol Chem [Internet]. 2014 Jan 17 [cited 2014 Jul 23];289(3):1203-11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24324257
163. Feng B, Yao PM, Li Y, Devlin CM, Zhang D, Harding HP, et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol [Internet]. 2003 Sep [cited 2014 Jul 26];5(9):781-92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12907943
164. Cunha DA, Hekerman P, Ladrière L, Bazarra-Castro A, Ortis F, Wakeham MC, et al. Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. J Cell Sci [Internet]. 2008 Jul 15 [cited 2014 Jul 27];121(Pt 14):2308-18. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3675788&tool=pmcentrez&rendertype=abstract
165. Park SW, Zhou Y, Lee J, Lee J, Ozcan U. Sarco(endo)plasmic reticulum Ca2+-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. Proc Natl Acad Sci U S A [Internet]. 2010 Nov 9 [cited 2014 Jul 22];107(45):19320-5. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2984194&tool=pmcentrez&rendertype=abstract
166. Wang Y, Vera L, Fischer WH, Montminy M. The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature [Internet]. 2009 Jul 23 [cited 2014 Jul 20];460(7254):534-7. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2730924&tool=pmcentrez&rendertype=abstract
167. Usui M, Yamaguchi S, Tanji Y, Tominaga R, Ishigaki Y, Fukumoto M, et al. Atf6a-null mice are glucose intolerant due to pancreatic ß-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism [Internet]. 2012 Aug [cited 2014 Jul 27];61(8):1118-28. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22386934
168. Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell [Internet]. 2001 Jun [cited 2014 Jul 27];7(6):1153-63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11430819
169. Zhang W, Feng D, Li Y, Iida K, McGrath B, Cavener DR. PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab [Internet]. 2006 Dec [cited 2014 Jul 27];4(6):491-7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17141632
170. Gao Y, Sartori DJ, Li C, Yu Q-C, Kushner JA, Simon MC, et al. PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis. Mol Cell Biol [Internet]. 2012 Dec [cited 2014 Jul 27];32(24):5129-39. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3510549&tool=pmcentrez&rendertype=abstract
171. Hosoi T, Miyahara T, Kayano T, Yokoyama S, Ozawa K. Fluvoxamine attenuated endoplasmic reticulum stress-induced leptin resistance. Front Endocrinol (Lausanne) [Internet]. 2012 Jan [cited 2014 Jul 8];3(January):12. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3355886&tool=pmcentrez&rendertype=abstract
172. Hosoi T, Yamaguchi R, Noji K, Matsuo S, Baba S, Toyoda K, et al. Flurbiprofen ameliorated obesity by attenuating leptin resistance induced by endoplasmic reticulum stress. EMBO Mol Med [Internet]. 2014 Mar;6(3):335-46. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3958308&tool=pmcentrez&rendertype=abstract
173. Hosoi T, Baba S, Ozawa K. Therapeutic potential of flurbiprofen against obesity in mice. Biochem Biophys Res Commun [Internet]. 2014 Jun 20 [cited 2014 Jul 27];449(1):132-4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24813992
174. Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, et al. Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes [Internet]. 2010 Aug [cited 2014 Jul 27];59(8):1899-905. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2911053&tool=pmcentrez&rendertype=abstract
175. Xiao C, Giacca A, Lewis GF. Sodium phenylbutyrate, a drug with known capacity to reduce endoplasmic reticulum stress, partially alleviates lipid-induced insulin resistance and beta-cell dysfunction in humans. Diabetes [Internet]. 2011 Mar [cited 2014 Jul 27];60(3):918-24. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3046853&tool=pmcentrez&rendertype=abstract
176. Howard JK, Lord GM, Matarese G, Vendetti S, Ghatei MA, Ritter MA, et al. Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J Clin Invest [Internet]. 1999 Oct [cited 2014 Sep 11];104(8):1051-9. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=408574&tool=pmcentrez&rendertype=abstract
177. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature [Internet]. 1998 Aug 27 [cited 2014 Sep 11];394(6696):897-901. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9732873
178. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest [Internet]. 1997 Jul 15 [cited 2014 Sep 11];100(2):270-8. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=508189&tool=pmcentrez&rendertype=abstract
179. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell [Internet]. 2000 Jan 21 [cited 2014 Aug 29];100(2):197-207. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10660043
180. Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet [Internet]. 1996 Mar [cited 2014 Sep 11];12(3):318-20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8589726
181. Bouloumié A, Drexler HC, Lafontan M, Busse R. Leptin, the product of Ob gene, promotes angiogenesis. Circ Res [Internet]. 1998 Nov 16 [cited 2014 Sep 11];83(10):1059-66. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9815153
182. Sierra-Honigmann MR, Nath AK, Murakami C, García-Cardeña G, Papapetropoulos A, Sessa WC, et al. Biological action of leptin as an angiogenic factor. Science [Internet]. 1998 Sep 11 [cited 2014 Sep 11];281(5383):1683-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9733517
183. Doherty GH, Oldreive C, Harvey J. Neuroprotective actions of leptin on central and peripheral neurons in vitro. Neuroscience [Internet]. 2008 Jul 17 [cited 2014 Sep 11];154(4):1297-307. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18550292
184. Weng Z, Signore AP, Gao Y, Wang S, Zhang F, Hastings T, et al. Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling. J Biol Chem [Internet]. 2007 Nov 23 [cited 2014 Sep 11];282(47):34479-91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17895242
185. Pérez-González R, Antequera D, Vargas T, Spuch C, Bolós M, Carro E. Leptin induces proliferation of neuronal progenitors and neuroprotection in a mouse model of Alzheimer's disease. J Alzheimers Dis [Internet]. 2011 Jan [cited 2014 Sep 11];24 Suppl 2:17-25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21335656
186. Guo Z, Jiang H, Xu X, Duan W, Mattson MP. Leptin-mediated cell survival signaling in hippocampal neurons mediated by JAK STAT3 and mitochondrial stabilization. J Biol Chem [Internet]. 2008 Jan 18 [cited 2014 Sep 11];283(3):1754-63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17993459
187. Greco SJ, Bryan KJ, Sarkar S, Zhu X, Smith MA, Ashford JW, et al. Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis [Internet]. 2010 Jan [cited 2014 Sep 11];19(4):1155-67. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2862270&tool=pmcentrez&rendertype=abstract
188. Kim JG, Suyama S, Koch M, Jin S, Argente-Arizon P, Argente J, et al. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat Neurosci [Internet]. 2014 Jul [cited 2014 Aug 19];17(7):908-10. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4113214&tool=pmcentrez&rendertype=abstract
189. Li C, Zhao R, Gao K, Wei Z, Yin MY, Lau LT, et al. Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer's disease. Curr Alzheimer Res [Internet]. 2011 Feb [cited 2014 Sep 11];8(1):67-80. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21143158
190. La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol [Internet]. 2004 May [cited 2014 Sep 10];4(5):371-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15122202
191. Matarese G, Sanna V, Di Giacomo A, Lord GM, Howard JK, Bloom SR, et al. Leptin potentiates experimental autoimmune encephalomyelitis in SJL female mice and confers susceptibility to males. Eur J Immunol [Internet]. 2001 May [cited 2014 Sep 11];31(5):1324-32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11465089
192. Frankenberry KA, Somasundar P, McFadden DW, Vona-Davis LC. Leptin induces cell migration and the expression of growth factors in human prostate cancer cells. Am J Surg [Internet]. 2004 Nov [cited 2014 Sep 11];188(5):560-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15546570
193. Mauro L, Catalano S, Bossi G, Pellegrino M, Barone I, Morales S, et al. Evidences that leptin up-regulates E-cadherin expression in breast cancer: effects on tumor growth and progression. Cancer Res [Internet]. 2007 Apr 1 [cited 2014 Sep 11];67(7):3412-21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17409452
194. Rene Gonzalez R, Watters A, Xu Y, Singh UP, Mann DR, Rueda BR, et al. Leptin-signaling inhibition results in efficient antitumor activity in estrogen receptor positive or negative breast cancer. Breast Cancer Res [Internet]. 2009 Jan [cited 2014 Sep 11];11(3):R36. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2716504&tool=pmcentrez&rendertype=abstract
195. Nordström V, Willershäuser M, Herzer S, Rozman J, von Bohlen Und Halbach O, Meldner S, et al. Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis. PLoS Biol. 2013;11(3):e1001506.
196. Liu Q, Zhang J, Zerbinatti C, Zhan Y, Kolber BJ, Herz J, et al. Lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis in the adult central nervous system. PLoS Biol. 2011;9(1):e1000575.