Obesidad monogénica humana: papel del sistema leptina-melanocortina en la regulación de la ingesta de alimentos y el peso corporal en humanos
Palabras clave:
Obesidad. leptina. melanocortinas. regulación de la ingesta. peso corporal.Resumen
La obesidad humana es un trastorno de origen multifactorial en el que intervienen factores tanto genéticos como ambientales. La existencia de alteraciones genéticas que dan origen a obesidades monogénicas resultan muy interesantes para el estudio de los mecanismos que contribuyan a un aumento de la ingesta de energía y la acumulación de grasa en el cuerpo. La mayoría de los genes implicados en obesidad monogénica se relacionan con el sistema de la leptina-melanocortinas, de ahí la importancia de su estudio a través de mutaciones naturales en ratones. Así, se han descrito mutaciones relacionadas con obesidad humana de tipo monogénica en la leptina y su receptor, proopiomelanocortina y prohormona convertasa 1. El objetivo de este trabajo ha sido ofrecer una revisión actualizada acerca de las principales características y funcionamiento del sistema leptina–melanocortinas, así como de sus implicaciones y potencialidades en el proceso de regulación de la ingesta alimentaria y control del peso corporal.Descargas
Citas
1. AGUILAR CORDERO MJ, GONZÁLEZ JIMÉNEZ E, GARCÍA GARCÍA CJ, GARCÍA LÓPEZ PA, ÁLVAREZ FERRE J, PADILLA LÓPEZ CA et al. Obesity in a school children population from Granada: assessment of the efficacy of an educational intervention. Nutr Hosp 2011; 26: 636-641.
2. AGUILAR CORDERO MJ, GONZÁLEZ JIMÉNEZ E, SÁNCHEZ PERONA J, PADILLA LÓPEZ CA, ÁLVAREZ FERRE J, MUR VILLAR N et al. The Guadix study of the effects of a Mediterranean-diet breakfast on the postprandial lipid parameters of overweight and obese pre-adolescents. Nutr Hosp 2010; 25: 1025-1033.
3. OCHOA MC, MARTÍ A, MARTÍNEZ JA. Estudios sobre la obesidad en genes candidatos. Med Clin (Barc) 2004; 122: 542-551.
https://doi.org/10.1016/S0025-7753(04)74300-6
4. RANKINEN T, ZUBERI A, CHAGNON YC, WEISNAGEL SJ, ARGYROPOULOS G, WALTS B. The human obesity gene map: the 2005 update. Obesity 2006; 14: 529-644.
https://doi.org/10.1038/oby.2006.71
5. MACNEIL DJ, HOWARD AD, GUAN X, FONG TM, NARGUND RP, BEDNAREK MA et al. Eur J Pharmacol 2002; 450: 93-109.
https://doi.org/10.1016/S0014-2999(02)01989-1
6. ROSADOC EL, MONTEIRO JB, CHAIA V, DO LAGO MF. Efecto de la leptina en el tratamiento de la obesidad e influencia de la dieta en la secreción y acción de la hormona. Nutr Hosp 2006; 21: 686-693.
7. BULLÓ BONET M. La leptina en la regulación del balance energético. Nutr Hosp 2002; 17 (Supl. 1): 42-48.
8. ROBERTSON SA, LEINNINGER GM, MYERS MG. Molecular and neural mediators of leptin action. Physiol Behav 2008; 94: 637-642.
https://doi.org/10.1016/j.physbeh.2008.04.005
9. CONE RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci 2005; 8: 571-578.
https://doi.org/10.1038/nn1455
10. SEELEY RJ, DRAZEN DL, CLEGG DJ. The critical role of the melanocortin system in the control of energy intake. Annu Rev Nutr 2004; 24: 133-149.
https://doi.org/10.1146/annurev.nutr.24.012003.132428
11. IVANOVA E, KELSEY G. Imprinted genes and hypothalamic function. J Mol Endocrinol 2011; 47: 67-74.
https://doi.org/10.1530/JME-11-0065
12. HUNG CC, LUAN J, SIMS M, KEOGH JM, HALL C, WAREHAM NJ et al. Studies of the SIM1 gene in relation to human obesity and obesity-related traits. Int J Obes (Lond) 2007; 31: 429-434.
https://doi.org/10.1038/sj.ijo.0803443
13. HOLDER JR JL, BUTTE NF, ZINN AR. Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet 2000; 9: 101-108.
https://doi.org/10.1093/hmg/9.1.101
14. GHOUSSAINI M, STUTZMANN F, COUTURIER C, VATIN V, DURAND E, LECOEUR C et al. Analysis of the SIM1 contribution to polygenic obesity in the French population. Obesity 2010; 18: 1670-1675.
https://doi.org/10.1038/oby.2009.468
15. TOLSON KP, GEMELLI T, GAUTRON L, ELMQUIST JK, ZINN AR, KUBLAOUI BM. Postnatal Sim1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression. Neurobiol Dis 2010; 30: 3803-3812.
https://doi.org/10.1523/JNEUROSCI.5444-09.2010
16. TAPIA-ARANCIBIA L, RAGE F, GIVALOIS L, ARANCIBIA S. Physiology of BDNF: focus on hypothalamic function. Front Neuroendocrinol 2004; 25: 77-107.
https://doi.org/10.1016/j.yfrne.2004.04.001
17. GRAY J, YEO GS, COX JJ, MORTON J, ADLAM ALR, KEOGH JM. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 2006; 55: 3366-3371.
https://doi.org/10.2337/db06-0550
18. HAN JC, LIU QR, JONES M. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med 2008; 359: 918-927.
https://doi.org/10.1056/NEJMoa0801119
19. ZHANG Y, PROENCA R, MAFFEI M, BARONE M, LEOPOLD L, FRIEDMAN JM. Positional cloning of the Mouse obese gene and its human homologue. Nature 1994; 372: 425-432.
https://doi.org/10.1038/372425a0
20. HALAAS JL, GAJIWALA KS, MAFFEI M, COHEN SL, CHAIT BT, RABINOWITZ D. Weight reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543-546.
https://doi.org/10.1126/science.7624777
21. MONTAGUE CT, FAROOQI IS, WHITEHEAD JP, SOOS MA, RAU H, WAREHAM NJ. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387: 903-908.
22. GONZÁLEZ JIMÉNEZ E, AGUILAR CORDERO MJ, GARCÍA GARCÍA CJ, GARCÍA LÓPEZ PA, ÁLVAREZ FERRE J, PADILLA LÓPEZ CA. Leptin: a peptide with therapeutic potential in the obese. Endocrinol Nutr 2010; 57: 322-327.
https://doi.org/10.1016/j.endonu.2010.03.018
23. OSWAL A, YEO GS. The leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics. Obes Rev 2007; 8: 293-306.
https://doi.org/10.1111/j.1467-789X.2007.00378.x
24. ANDIRAN N, CELIK N, ANDIRAN F. Homozygosity for two missense mutations in the leptin receptor gene (P316:W646C) in a Turkmenian girl with severe early-onset obesity. J Pediatr Endocrinol Metab 2011; 24: 1043-1045.
https://doi.org/10.1515/JPEM.2011.313
25. WITHERS DJ, GUTIERREZ JS, TOWERY H, BURKS DJ, REN JM, PREVIS S. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998; 391: 900-904.
26. REN D, LI M, DUAN C, RUI L. Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Cell Metab 2005; 2: 95-104.
https://doi.org/10.1016/j.cmet.2005.07.004
27. GANTZ I, FONG TM. The melanocortin system. Am J Physiol Endocrinol Metab 2003; 284: 468-474.
https://doi.org/10.1152/ajpendo.00434.2002
28. HUSZAR D, LYNCH CA, FAIRCHILD-HUNTRESS V, DUNMORE JH, FANG Q, BERKEMEIER LR. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88: 131-141.
https://doi.org/10.1016/S0092-8674(00)81865-6
29. VAISSE C, CLEMENT K, GUY- GRAND B, FROGUEL P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 1998; 20: 113-114.
30. MARTÍ A, CORBALÁN MS, FORGA L, MARTÍNEZ JA, HINNEY A, HEBEBRAND J. A novel nonsense mutation in the melanocortin-4 receptor associated with obesity in a Spanish population. Int J Obes 2003; 27: 385-388.
https://doi.org/10.1038/sj.ijo.0802244
31. BRUMM H, MÜHLHAUS J, BOLZE F, SCHERAG S, HINNEY A, HEBEBRAND J et al. Rescue of Melanocortin 4 Receptor (MC4R) Nonsense Mutations by Aminoglycoside-Mediated Read-Through. Obesity (Silver Spring) 2012; 20: 1074-1081.
https://doi.org/10.1038/oby.2011.202
32. TAO YX. Mutations in the melanocortin-3 receptor (MC3R) gene: Impact on human obesity or adiposity. Curr Opin Investig Drugs 2010; 11: 1092-1096.
33. BOCHUKOVA EG, HUANG N, KEOGH J, HENNING E, PURMANN C, BLASZCZYK K et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 2010; 463: 666-670.
https://doi.org/10.1038/nature08689
34. MILLINGTON GWM. The role of proopiomelanocortin (POMC) neurones in feeding behaviour. Nutr Metab 2007; 4: 18.
https://doi.org/10.1186/1743-7075-4-18
35. CHOQUET H, STIJNEN P, CREEMERS JW. Genetic and functional characterization of PCSK1. Methods Mol Biol 2011;768: 247-253.
https://doi.org/10.1007/978-1-61779-204-5_13
36. COWLEY MA, SMART JL, RUBINSTEIN M, CERDÁN MG, DIANO S, HORVATH TL. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001; 411: 480-484.
https://doi.org/10.1038/35078085
37. LAUTENBACH A, BREITMEIER D, KUHLMANN S, NAVE H. Human obesity reduces the number of hepatic leptin receptor (ob-R) expressing NK cells. Endocr Res 2011; 36:158-166.
https://doi.org/10.3109/07435800.2011.580442
38. WAUMAN J, TAVERNIER J. Leptin receptor signaling: pathways to leptin resistance. Front Biosci 2011; 1: 2771-2793.
39. MYERS MG. Keeping the fat off with nesfatin. Nat Med 2006; 12: 1248-1249.
https://doi.org/10.1038/nm1106-1248
40. XU B, GOULDING EH, ZANG K, CEPOI D, CONE RD, JONES KR. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 2003; 6: 736-742.
https://doi.org/10.1038/nn1073
41. HU Y, RUSSEK SJ. BDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulation. J Neurochem 2008; 105: 1-17.
https://doi.org/10.1111/j.1471-4159.2008.05237.x
42. HAN JC, LIU QR, JONES M, LEVINN RL, MENZIE CM, JEFFERSON-GEORGE KS, ET AL. Brain derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med 2008; 359: 918-927.
https://doi.org/10.1056/NEJMoa0801119
43. YEO GS, CONNIE HUNG CC, ROCHFORD J, KEOGH J, GRAY J, SIVARAMAKRISHNAN S. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 2004; 7: 1187-1189.
https://doi.org/10.1038/nn1336
44. GRAY J, YEO GS, COX JJ, MORTON J, ADLAM ALR, KEOGH JM ET AL. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 2006; 55: 3366-3371.
https://doi.org/10.2337/db06-0550
45. NOBLE EE, BILLINGTON C, KOTZ CM, WANG C. The lighter side of BDNF. Am J Physiol 2011; 300: 1053-1069.
https://doi.org/10.1152/ajpregu.00776.2010
46. FAROOQI IS, JEBB SA, LANGMACK G, LAWRENCE E, CHEETHAM CH, PRENTICE AM. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879-884.
https://doi.org/10.1056/NEJM199909163411204
47. DONATO J JR, CRAVO RM, FRAZÃO R, ELIAS CF. Hypothalamic sites of leptin action linking metabolism and reproduction. Neuroendocrinology 2011; 93: 9-18.
https://doi.org/10.1159/000322472
48. DHILLON SS, MCFADDEN SA, CHALMERS JA, CENTENO ML, KIM GL, BELSHAM DD. Cellular leptin resistance impairs the leptin-mediated suppression of neuropeptide y secretion in hypothalamic neurons. Endocrinology 2011; 152: 4138-4147.
https://doi.org/10.1210/en.2011-0178
49. SCHUSTER B, KOVALEVA M, SUN Y, REGENHARD P, MATTHEWS V, GRÖTZINGER J et al. Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF. J Biol Chem 2003; 278: 9528-9535.
https://doi.org/10.1074/jbc.M210044200
50. REINEHR T, HEBEBRAND J, FRIEDEL S, TOSCHKE AM, BRUMM H, BIEBERMANN et al. Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene. Obesity 2009; 17: 382-389.
https://doi.org/10.1038/oby.2008.422
51. BECKERS S, ZEGERS D, VAN GAAL LF, VAN HUL W. The role of the leptin-melanocortin signalling pathway in the control of food intake. Crit Rev Eukaryot Gene Expr 2009; 19: 267-287.
https://doi.org/10.1615/CritRevEukarGeneExpr.v19.i4.20
52. GONZÁLEZ JIMÉNEZ E. Genes and obesity: a cause and effect relationship. Endocrinol Nutr 2011; 58: 492-496.
https://doi.org/10.1016/j.endonu.2011.06.004
53. ZURBANO INCHUSTA R, OCHOA NIETO MC, MORENO-ALIAGA MJ, MARTI DEL MORAL A. Estudios sobre obesidad de origen monogénico en humanos. Rev Esp Obes 2004; 2: 269-278.
Publicado
Cómo citar
Número
Sección
Licencia
Derechos de autor 2012 Anales del Sistema Sanitario de Navarra
Esta obra está bajo una licencia internacional Creative Commons Atribución-CompartirIgual 4.0.
La revista Anales del Sistema Sanitario de Navarra es publicada por el Departamento de Salud del Gobierno de Navarra (España), quien conserva los derechos patrimoniales (copyright ) sobre el artículo publicado y favorece y permite la difusión del mismo bajo licencia Creative Commons Reconocimiento-CompartirIgual 4.0 Internacional (CC BY-SA 4.0). Esta licencia permite copiar, usar, difundir, transmitir y exponer públicamente el artículo, siempre que siempre que se cite la autoría y la publicación inicial en Anales del Sistema Sanitario de Navarra, y se distinga la existencia de esta licencia de uso.
