3. Liver
Bone
Adipose
Tissue
Skeletal muscle

4. Diurnal Rhythm of GH
+100%
V
A
R
I
A 0
T
I
O
N
-100%
12 midnight 6am 12 noon 6pm 12 midn

5. GH - Secreción Pulsatil
l ________ Regular Fed Day ______Fasting Day
l Pulsos son regulados por GHRH, Ghrelina y Somatostatina
l Feedback por IGF-l, Leptina y la GH misma
l Hartman ML, Veldhuis JD, Thorner MO. Hormone Research 40: 37-47 1993.

9. EJERCICIO
SUEÑO
HIPOGLICEMIA
(+)
(-)
(-) HIPOTALAMO
SOMATOSTATINA GHRH
(-) (+)
PITUITARIA (+) GHRELINA
GH
HIGADO
IGF´s
ESTIMULA LA BLOQUEA LA ENTRADA
AUMENTA LA DE GLUCOSA EN
SINTESIS DE
GLUCONEOGENESIS EL TEJIDO ADIPOSO
PROTEINAS

10. LOS AZUCARES
PASAN MAS
RAPIDAMENTE A
LA CIRCULACION
QUE LAS
PROTEINAS

11. Blood concentrations of ghrelin are lowest shortly after
consumption of a meal, then rise during the fast just prior to
the next meal. The figure shows this pattern based on assays
of plasma ghrelin in 10 humans during the course of a day.

12. Núcleo
Para
Ventricular
Área
Hipotalámica
Lateral
Hipotálamo
VentroMedial
Locus
Coeruleus
Núcleo
Motor
Dorsal
del
Nervio
Vago
Núcleo
Tracto
Solitario

13. GHRELINA
PRODUCIDA EN
ESTOMAGO, CEREBRO
(HIPOTALAMO), INTESTINO Y
PANCREAS
VIA OREXIGENICA (ESTIMULADORA
DEL APETITO) DEL NUCLEO
ARCUATO
Neuropeptide Y (NPY) and
Agouti-Related Protein (AGRP)
Insulin
LEPTINA
PRODUCIDA EN TEJIDO ADIPOSO
VIA ANOREXIGENICA
Pro-opiomelanocortina
(POMC)
y Cocaine- and Amphetamine
Regulated Transcript (CART)
5HT
NUCLEO VENTROMEDIAL = CENTRO
DE LA SACIEDAD

14. Receptors for ghrelin have been found on NPY neurones in the hypothalamic arcuate
nucleus, a major brain area involved in the control of appetite. The NPY neurones are
potent stimulators of appetite and upon activation by ghrelin they inhibit the POMC
neurones by releasing the inhibitory neurotransmitter GABA which inhibits the release
of alpha MSH, an inhibitor of appetite. Ghrelin also activates the release of AgRP
which is an antagonist of the alpha MSH receptors MC3 and MC4, blocking alpha
MSH from activating its receptor and inhibiting appetite

15. α2-­‐AR,
α2-­‐adrenergic
receptor;
β3-­‐AR,
β3-­‐
adrenergic
receptor;
AC,
adenyl
cyclase;
ACh,
acetylcholine;
cAMP,
cyclic
AMP;
Ca++,
calcium
ions;
DAG,
diacylglycerol;
DMV,
dorsal
motor
nucleus
of
the
vagus
nerve;
FFA,
free
faBy
acids;
Gi,
inhibitory
G
protein;
GK,
glucokinase;
GLP-­‐1,
glucagon-­‐like
pepFde
1;
GLP-­‐1R,
GLP-­‐1
receptor;
Glu-­‐6-­‐PO4,
glucose-­‐6-­‐phosphate;
Glut4,
glucose
transporter
4;
+
HSL,
hormone-­‐sensiFve
lipase;
IML,
intermediolateral
cell
column;
IP3,
inositol
triphosphate;
K
,
potassium
ions;
KATP,
ATP-­‐
dependent
potassium
channel;
LC,
locus
coeruleus;
LHA,
lateral
hypothalamic
area;
LPL,
lipoprotein
lipase;
M1
and
M3,
muscarinic
receptors;
MARCKS,
myristoylated
alanine-­‐rich
protein
kinase
C
substrate;
Na+,
sodium
ions;
NE,
norepinephrine;
PIP2,
phosphaFdylinositol
pyrophosphate;
PKA,
protein
kinase
A;
PKC,
protein
kinase
C;
PLC,
phospholipase
C;
PVN,
paraventricular
nucleus;
SNS,
sympatheFc
nervous
system;
SS5R,
somatostaFn
receptor
type
5;
SUR,
sufonylurea
receptor;
TG,
triglyceride;
VCa,
voltage-­‐gated
calcium
channel;
VMH,
ventromedial
hypothalamus.

16. β3-Adrenergic Receptor
White Adipose Tissue

17. Response to Leptin therapy in Congenital
leptin deficiency

20. HIPOTALAMO
NPY CRH
HIPOFISIS
POMC
ACTH
ADRENALES
GLUCAGON
AUMENTO DE GC INHIBICION DE CAPTACION
GLUCONEOGENESIS DE GLUCOSA
POR TEJIDOS PERIFERICOS
PROTEOLISIS EN TEJIDOS AUMENTO DE LIPOLISIS
PERIFERICOS (SUMINISTRO ADIPOCITARIA, PERO EN
DE SUSTRATOS FORMA CRONICA
GLUCONEOGENICOS)

21. ADIPOCITO
INSULINA OB
LEPTINA
Ob-R
STAT3
ENDOCANABINOIDES
Signal transducer
& activator of transcription
ANANDAMIDE
2-ARACHIDONYL GLYCEROL

22. HIPOTALAMO
GHRH
SRIF TRH
TESTOSTRONA
CORTISOL
AG. GRASOS
? HIPOFISIS
PRL GH
GHS
HIGADO
IGF
TEJIDOS PERIFERICOS

23. ­ GH ↑ metabolismo de lípidos
↑ energía
Adipocito
Trigliceridos
Ac. grasos
GH
R Acetatos
CoA
Acetil CoA
Ciclo
de
Krebs

24. ­ GH ↓ metabolismo de CHO
MAS
IMPORTANTE
ESTE
SUMINISTRO
Glicogeno
Glucosa 6-PO4
Ac. Grasos
Glucosa
Glut Glucosa Acetatos
CoA
Glucosa 6-PO4
Ac. Piruvico Acetil CoA
Ciclo
de
CO2 + ácido Krebs
láctico + Energía

28. Focal Adhesion Kinase
cytoskeletal reorganization,
cell migration, chemotaxis,
mitogenesis, and/or prevention
of apoptosis and gene
transcription.
Suppressor
of cytokine
signalling
Gamma-
interferon-
activated
sequence
(GAS)-like
element (GLE)

29. [A] GH
GH GH
GH GHGH GH GH
P P
P
Unión de P
[B] GH ⇒ JAK2 TYK2 y fosforilación
fosforilación por JAK2
dimeriza-
[C] [D]
ción; JAK2/
TYK2
activación
= receptor monomero
= TYK2
= JAK
JAK = Janus-associated kinase
TYK2 = Tyrosine kinase 2

30. [A] [B]
GH GH GH GH
P P P P
STAT STAT P STAT P STAT
P STAT P P P P
P STAT
P STAT P STAT P P P
STAT PP P
P STAT
STAT STAT P STAT P
P
STAT [C] dimer formation STAT
STAT P STAT P
P Stat dimero STAT
P NUCLEO
= receptor monomero
[D]
= TYK2 translocación
= JAK [E] EFECTOS
P IGF-1 release (liver)
= STAT P lipolysis (adipose)
a.a. uptake (muscle)
Signal transducer
& activator of transcription

32. calcium release-activated Ca2+
importin a/b and RanGDP
Interferon
Gamma
Activated
Sequence

34. INYECCION DE ARG
Mide la capacidad de la pituitaria para secretar GH

35. Panhipopituitarismo: deficiencia de las hormonas de la hipofisis
anterior
No hay aumento de GH en respuesta a la hipoglicemia
Inyecciones de GH tres veces por semana
Tratmiento con GH

38. Miércoles 6 de Febrero, 2007

42. PROTEINAS
CORPORALES
Degradación
Reutilización
Proteica
CRECIMIENTO para nueva
(20-35 g/día
síntesis
de N)
proteica
(15-25 g/día
AMINOACIDOS de N)
Alimentación
AA con equilibrio
ENERG/PROT CATABOLISMO
(5-7 g/día N)

43. " ASOCIADO A
PROTEINA G
" ESTIMULA LA
FORMACION DE
AMPc
" EXPRESADO EN
LA PITUITARIA

44. MEMBRANA
Ca++/CaM
PK P GH
AMPc
GHRH R
SRIF R AMP
ATP

45. HIPOTALAMO
Nucleo
Area Periventricular
Arcuato
GHRH SRIF Arriba del quiasma optico
↑cAMP ↓cAMP
Células
Somatotrofas
secretan GH
Feedback
negativo Feedback
GH unida positivo
a GHBP
Feedback
JAK negativo
Higado
IGF-1  huesos y músculo

46. GHRH SRIF
Receptor α2 receptor
β1 or β2
Gs Gi
β
αs β αi β
β β
γ γ
γ γ
GTP GTP
αi
CELULAS αs
GTP GTP
SIMATOTROFAS
⊕ 
Adenilato Adenilato Adenilato
cyclasa ciclasa
Activa
cyclasa
inactiva inactiva
ATP AMPc

47. Adenilato CREB = Cyclic AMP Responsive
ciclasa Element Binding protein
ACTIVA
ATP AMP ciclico
É
Proteina Kinasa A Activa GH secretion
HO CREB ATP
PO CREB NUCLEO
PO OP
PO
PO OP OP
Sintesis de
GH
Aumento de la transcripción del gen de la GH

49. L-­‐692,429
FIG.
3.
Fluorescent
raFo
imaging
showing
the
effect
of
L-­‐692,429
on
cytoplasmic
free
Ca21
in
a
rat
somatotroph.
Images
of
a
somatotroph
at
340
nm
and
380
nm
are
shown
as
a
funcFon
of
Fme
aUer
addiFon
of
L-­‐692,429.
The
concentraFon
of
L-­‐692,429
selected
was
33-­‐fold
theEC50
for
GH
release,
and
the
free
intracellular
Ca21
increased
from
approximately
100
to
780
nM
(29).
[Reprinted
with
permission
from
R.
G.
Smith
et
al.:
Science
260:1640–1643
(29).
©
1993
American
AssociaFon
for
the
Advancement
of
Science.]

50. Spiroindanos

51. MK-­‐0677
• Su
receptor
actúa
vía
proteina-­‐G,
acFvando
a
la
PLC

56. Pituitary specific transcription factor 1

58. Potential mechanisms mediating the antitumorigenic actions of GHRH antagonists (GHRH-
Ant).
Kineman R D PNAS 2000;97:532-534
©2000 by The National Academy of Sciences

60. (phosphatase and tensin
homolog deleted on
chromosome 10)

61. PI3K
Phosphatase
and tensin homologue
eukaryotic translation
Target Of
initiation factor 4E binding protein
Rapamycin
eukaryotic translation
initiation factor 4E

62. • EL DOMINIO KINASA
DEL RECEPTOR
(IGF1-R) COMPARTE
84% DE HOMOLOGIA
CON EL DE LA
INSULINA
• EL IGF-1 SE PUEDE
UNIR AL RECEPTOR
DE LA INSULINA Y
VICEVERSA (PERO
CON MUCHO MENOS
AFINIDAD)

63. Figure 3 Potential insulin/IGF-1 signaling pathways in the pancreatic [beta]-cell
sarco-endoplasmic reticulum
calcium ATPase
hepatocyte nuclear factor
Biochemical Society Transactions Biochem. Soc. Trans. (2002) 30, 317-322

64. EXPRESION DE LOS RECEPTORES
LA DENSIDAD DE LOS RECEPTORES AL IGF-I REVELA UN
PATRON ESPECIFICO DE LOS TEJIDOS A LO LARGO DEL
DESARROLLO

65. BIOENSAYOS
(IGF)
" MEDIDA DE LA
INCORPORACION
DE SO435 EN EL
CARTILAGO
PELVICO DE
POLLO CON
SUERO
" DOSIFICACIONES
DE LA BINDING
PROTEIN DEL IGF-I

67. IGFBP-related proteins Acid Labile Subunit

68. IGFBP-1
EXTIENDE LA VIDA MEDIA DE LOS IGF´s

70. Platelet-derived Growth Factor

71. phosphoinositide-dependent protein kinase
Phosphoinositide-3-kinase
Serum and glucocorticoid-inducible kinase (SGK)

72. Fig.1. IGF signaling is sufficient and required for anterior development in Xenopus
embryos. (A) Secondary head-like structure induced after microinjection of
400 pg IGF2 mRNA into one ventral blastomere at the 4-cell stage. cg,
secondary cement gland; ey, ectopic eye. (B) Uninjected 3-day tadpole.
(C) Embryo injected with 500 pg dominant negative IGF type 1 receptor
(DNIGF) mRNA per animal blastomere at the 4-8 cell stage showing reduction of
cement gland and eye structures. (From Pera et al. (2001) Dev. Cell)

73. Figura 6. IGF-I y "miogénesis" durante la hipertrofia compensatoria. Grandes cargas conllevan a la proliferación,
diferenciación, y fusión de las células "satélite". La IGF-I se ha demostrado que estimula estos procesos miogénicos
en los músculos esqueléticos. Se ha postulado que la IGF-I y/o la isoforma IGF-I factor de crecimiento mecánico sensible
a la sobrecarga (mechano growth factor, MGF), es producida y liberada por las miofibras en respuesta a una carga mayor
o estiramiento. La mayor concentración local de IGF-I (MGF) estimularía entonces los procesos miogénicos necesarios para
dirigir la respuesta de la hipertrofia.