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UNIVERSIDAD CENTRAL DE VENEZUELAFACULTAD DE MEDICINA
ESCUELA DE MEDICINA “LUIS RAZETTI”CÁTEDRA DE FISIOLOGIA
Emilia Díaz19 de Febrero2013
SISTEMA ENDOCRINO Y METABOLISMOTEMA 10
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HORMONA DE CRECIMIENTOCONTENIDO PROGRAMÁTICO Hipófisis anterior. Relación hipotálamo hipófisis. Principales núcleos
hipotalámicos y principales células secretorias de la hipófisis. Modelo de desarrollo de la pituitaria anterior (anatomía y embriología)
Hormona de Crecimiento (HC). Variantes moleculares, secreción y transporte de la hormona del crecimiento en la sangre .
Control de la secreción hipofisiaria: GHRH y somatostatina. Factores fisiológicos que regulan la secreción
Receptor de la hormona del crecimiento (RHC). Vías de señalizaciòn: JAK2/STATs; proteínas SOCS
Efectos fisiológicos. Acciones metabólicas de la HC. Las somatomedinas (IGFs). Neurobiología del IGF-1. Transducción de la señal
hormonal: receptor, dimerización del receptor, ruta Jak/STAT. Eje HC-IGFBP-IGF (regulación).Efectos fisiológicos de los IGFs. La somatopausia: modelo esquemático de los mecanismo involucrados.
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HIPOTÁLAMO/HIPÓFISIS
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neurohipófisisadenohipófisis
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HIPOFISIS• Desarrollo 2 orígenes:
– Evaginación del ectodermo por delante de la membrana bucofaríngea bolsa de Rathke.
– Una prolongación del diencéfalo infundíbulo.
• 3° semana bolsa de Rathke se evagina en la cavidad bucal y crece en sentido dorsal hacia el infundíbulo.
• 2° mes pierde su conexión con la cavidad bucal y se haya en contacto con el infundíbulo.
• Adenohipófisis células de la pared anterior de la bolsa de Rathke
• La parte posterior de la bolsa de Rathke se convierte en la pars intermedia.
• El infundíbulo da origen a la neurohipófisis.
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Cohen, L. E. et al. Endocr Rev 2002;23:431-442
pituitaria fetal
DESARROLLO DE LA PITUITARIA FETALPROCESO AUTÒNOMO.
9ª semana
6ª semana
8ª semana
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HORMONA DEL CRECIMIENTO
CROMOSOMA 17
GH hipofisiariaSangre y SNC
Período postnatal
191 aa22 KDa
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Gene Producto Variantes(s) Tejido
hGH-N or GH1 HC normal
2 alternatively spliced variants (97): 22 kDa (full-length 191 aa); 20 kDa (lacking residues 32-46)
Hipófisis anterior
hGH-V or GH2 Variantes de la HCdetectables en el
embarazo desde la mitad hasta el parto
20 kDa Placenta
sincitiotrofoblasto (células)
CSH-1, CSH-2 Chorionic
somatotropin/human placental lactogen
22 kDa
Placenta sincitiotrofoblasto
(células)
CSH-like gene CSHL-1 proteinas no funcional Variantes alternativas
CINCO GENES PARA LA HC HUMANA
http://www.endotext.org/neuroendo/neuroendo1/neuroendoframe1.htm
CROMOSOMA 17
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TACE (enzima convertidora de TNF-α)
growth hormone binding protein
GHBP-1 GHBP-2PROTEINAS DE TRANSPORTE DE LA GH
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DIMORFISMO SEXUAL
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Factores que afectan la secreción de la HC
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REGULACIÓN DE LA
SECRECIÓN DE LA GH
INTERACCIÓN GHRH-SRIF
GH
HIPOTÁLAMO
HIPÓFISIS
SS
GHRH
SS
GHRH
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Neural Control
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Cromosoma 20
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LIBERACIÒN
SINTESIS
PROLIFERACIÓN
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SINTESIS Y SECRECIÓN
Modificado de Nature Reviews Cancer 2, 836-849 (November 2002)
Ca++
K+
SSTR2
LIBERACIÒN
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Factores fisológicos que en el humano cambian la secreción de la de
GH en humanos
HIPERGLICEMIA
HIPOGLICEMIA
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NEUROTRANSMISORES
NA
RECEPTOR ALFA-2RECEPTOR BETA
SS- +
SS
GHRH release
GH GHACh
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Regulation of the hypothalamic-
pituitary-growth hormone axis.
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RECEPTORES DE LA HORMONA DEL CRECIMIENTO
(GHR)
Clase IReceptores de
citoquinas
EN EL HUMANO SE EXPRESA ENHIGADORIÑÒNCORAZÓNMÚSCULO ESQUELÉTICOINTESTINOPULMÓNPANCREAS
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GHR
CROMOSOMA 5
Brooks and Waters,2010
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Brooks and Waters,2010
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Ahmed and Farquharson, 2010
Inhibición de las señales de transducción de la HC por las SOCS
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ESTRUCTURA DE LAS PROTEINAS SOCS
(SUPPRESSOR OF CYTOKINE SIGNALLING)
Modificado de Ahmed and Farquharson, 2010
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Model of GHR-Negative Regulation GHR ubiquitination and internalization occurs constitutively, in the absence of GH and it is enhanced upon GH binding.
Flores-Morales A et al. Molecular Endocrinology 2006;20:241-253©2006 by Endocrine Society
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Mol. Endocrinol. 2006 20 (2) 241-253
REGULACIÓN DE LA EXPRESIÓN DE GHR
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EFECTOS FISIOLÓGICOS DE LA HORMONA DEL CRECIMIENTO
DIRECTOS
La estimulación de1.- la producción de IGF en el hígado y otros tejidos2. - hidrólisis de triglicéridos en tejido adiposo3.- producción de glucosa en el hígado
Potenciados por los glucocorticoides, y se oponen a los de la insulina (y los IGF) en el metabolismo de los carbohidratos
(Davidson, 1987).
HC antagoniza la acción de la insulina directamente (bloqueando los mecanismos de señalización intracelulares) e indirectamente
(aumentando la lipolisis en los adipocitos).
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INDIRECTOS
Los efectos anabólicos y favorecedores del crecimiento de la hormona son efectos indirectos mediados por IGF-1. La condrogénesis, y el crecimiento del esqueleto y de tejidos blandos, dependen de manera directa del IGF-1.
Son parecidos a los de la insulina (Davidson, 1987) y, a diferencia de los efectos directos, son inhibidos por los glucocorticoides.
En casi todos los tejidos la hormona del crecimiento tiene el efecto de aumentar el número de las células, más que su tamaño, a través de IGF- 1.
EFECTOS FISIOLÓGICOS DE LA HORMONA DEL CRECIMIENTO
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LeRoith D and Yakar S (2007) Mechanisms of Disease: metabolic effects of growth hormone and insulin-like growth factor 1 Nat Clin Pract Endocrinol Metab 3: 302–310 doi:10.1038/ncpendmet0427
GH ACCIONES DIRECTAS
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LeRoith D and Yakar S (2007) Nat Clin Pract Endocrinol Metab 3: 302–310 doi:10.1038/ncpendmet0427
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PAPEL DE LA HORMONA DEL
CRECIMIENTO EN EL METABOLISMO
Vijayakumar y col 2011
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PEREZ-CASTRO ET AL. Physiol Rev • VOL 92 • JANUARY 2012 • www.prv.org 3
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FACTORES DE CRECIMIENTO TIPO INSULINA (IGF)
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70 aa
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Regulation of circulating and tissue levels of insulin-like growth factors
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60% amino acid sequence homology with the insulin receptor
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http://spider.science.strath.ac.uk/sipbs/staff/James_Beattie.htm
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http://www.ohsu.edu/xd/health/services/doernbecher/research-education/research/research-labs/ron-rosenfeld-lab.cfm
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LeRoith D and Yakar S (2007) Mechanisms of Disease: metabolic effects of growth hormone and insulin-like growth factor 1 Nat Clin Pract Endocrinol Metab 3: 302–310 doi:10.1038/ncpendmet0427
The actions of IGF1
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Ohlsson y col., 2009(Endocrine Reviews 30: 494–535, 2009)
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Eje GH-IGFBP-IGF crecimiento
IGF-I acts via autocrina y paracrinapara estimular la divisiòn celular
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A model for neurotrophic and neuroprotective actions of IGF-I in brain.
Russo V C et al. Endocrine Reviews 2005;26:916-943
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LA SOMATOPAUSIA
20-24 SEMANAS8 SEMANAS
20-30 AÑOS
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Perrini y col. 2010
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GRACIAS
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© 2005 Elsevier
catabolismo
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Anthony P. Heaney & Shlomo MelmedNature Reviews Cancer 4, 285-295 (April 2004)
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Regulación de la Secreción de la HC
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.
Conover C A Am J Physiol Endocrinol Metab 2008;294:E10-E14©2008 by American Physiological Society
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MODULADORES METABÓLICOS
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Fetal growth
• is a complex process involving maternal, placental and fetal factors.
• 1 The mechanisms underlying human fetal growth retardation remain unknown in many cases.2 In mammals, the insulinlike
• growth factor (IGF) system plays a crucial role in growth and development. The IGF system is
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Handwerger, 2009
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EFECTOS DE LA HC SOBRE EL METABOLISMO DE LOS AGL