Post on 14-Dec-2015
Regulation of IGF and IGF binding protein gene expression by Regulation of IGF and IGF binding protein gene expression by
nutrition and aquaculture related stressors: nutrition and aquaculture related stressors:
Implications in fish growth and stress assessment Implications in fish growth and stress assessment
Cunming Duan
University of Michigan, Ann Arbor, MI
Genotype Environmental factors
Growth
Food
Growth hormone (GH) transgenic animals
IGFs
GH
Extra-hepatic tissues(somatic, gonadal)
Liver
Brain
Environment
IGFs
The growth-promoting action of GH in postnatal stages is mediated The growth-promoting action of GH in postnatal stages is mediated by Insulin-like growth factors (IGFs)by Insulin-like growth factors (IGFs)
"Somatomedin Hypothesis""Somatomedin Hypothesis"
"Endocrine""Endocrine"
"Paracrine, autocrine""Paracrine, autocrine"
+
+
-
Duan (1997) Am. Zool.
pituitary
Insulin-like Growth Factor-1
B-domain
C-domain
A-domain
D-domain
G
P
E
T
L
GA
EL V D A L Q F
V
GD
R
G
F
Y
F
N
K
P
TG
YGSSSRRA
PQ
TG
I
V
D
E
C
F
R
S
DL
RR
LE
M
YC
A
P
L
K
P
AKSA
C
C
C
C
GrowthDevelopment ReproductionAging
IGF1R
IGF-1
Insulin-like Growth Factor (IGF) Signaling:
IGF-2
The IGF signaling is a evolutionarily conserved pathway that plays fundamental roles in growth control
The IGF signaling is a evolutionarily conserved pathway that plays fundamental roles in growth control
IGF-IR deficientIGF-IR deficientControlControl
Schlueter et al., FASEB J, 2006
Woods et al., N Engl J Med, 1996
Abuzzahab et al., N Engl J Med, 2003
Walenkamp et al., JCEM, 2005
Sutter et al., Science, 2007
Liu et al., Cell, 1993 Baker et al., Cell, 1993
IGFs
GH
Extra-hepatic tissues(somatic, gonadal)
Liver
Brain
Environment
IGFs
IGFs mediate GH actions in postnatal stagesIGFs mediate GH actions in postnatal stages
"Endocrine""Endocrine"
"Paracrine, autocrine""Paracrine, autocrine"
+
+
-pituitary
J. Nutrition, 1998
_
+ elevated levels- reduced levels? unknown
IGFs
GHIGFs
Extra-hepatic tissue growth(muscle, bone, gonad etc.)
Liver
Brain
Environment
Wood, A.W., Duan, C., and Bern, H.A. (2005). Insulin-like growth factor signaling in fish. Int. Rev. Cyto. 243: 215-285
StarvationUndernourishment Malnourishment
IGF-1 expression is also regulated by nutritional factors
pituitary
IGFs
GHIGFs
Extra-hepatic tissue growth(muscle, bone, gonad etc.)
Liver
Brain
Environment
IGF-1 expression is also regulated by nutritional factors
StarvationUndernourishment Malnourishment
Wood, A.W., Duan, C., and Bern, H.A. (2005). Insulin-like growth factor signaling in fish. Int. Rev. Cyto. 243: 215-285
pituitary
The hepatic expression IGF-1 is under the dual regulation The hepatic expression IGF-1 is under the dual regulation of nutrients and GHof nutrients and GH
IGFs
GHIGFs
Extra-hepatic tissues
Liver
Brain
Environment
Nutrients
•The nutritional regulation of the GH-IGF-I axis is an interface between nutrients and hormones acting in concert to control animal growth.
•This interface is conserved throughout vertebrate evolution.
pituitary
IGFs are bound to IGF binding proteins (IGFBP) in IGFs are bound to IGF binding proteins (IGFBP) in extracellular fluids extracellular fluids
BP
IGF
ALS
BP
IGF IGF
•Regulate the biological activities of IGFs by controlling their access to the IGF-1 receptors on target cells.
•Prolong the half-life of IGFs.
IGFBP-1
Hypoxia
.1
1
10
100 *
Hypox
ia
Norm
oxia
IGF
BP
-1 m
RN
A/ß
-act
in m
RN
A (
fold
)
Normoxia
Maures and Duan, 2002, Endocrinology
Kelley et al., 2002, J. Endocrinology
IGFBP-1 is induced by stressors
Low O2 Normal O2
IGFBP-1 is a hypoxia-inducible gene in zebrafish fish embryos and larvae
Kajimura et al. PNAS, 2005
96 hpf
Kajimura et al., PNAS (2005); Kajimura and Duan Fish Biol. (2007)
(1) Induction of IGFBP-1
IGF receptor
(2) Reduced “available” IGF
(3) Reduced IGF signaling
(4) Suppression of IGF actions
(5) Growth retardation Developmental delay
BP
-1
BP
-1
BP
-1
BP
-1
Catabolic or stressful conditions
IGFBP-1 is a metabolically controlled molecular switch IGFBP-1 is a metabolically controlled molecular switch that inhibits IGF actions under catabolic states that inhibits IGF actions under catabolic states
Fasting induces and re-feeding reduces IGFBP-1 gene expression in young zebrafish
Kamei, Lu, Jiao, et al., PLoS One, 2008
Experimental Design
2 month-old fish were fed with various rations (1, 3, and 9% of body weight) for 4 weeks
1-month old juvenile fish were fed with different diets. They are standard diet followed with:
high vs. low carbohydrate;high vs. low protein;
high vs. low fat;high vs. low vitamin contents
4 fish were sacrificed and their IGFBP-1a/-1b mRNA levels were measured by qRT-PCR and normalized by β-actin mRNA levels
At each sampling time, 20 fish were randomly picked up to measure their body length and body weight at each time point
40-50 fish in each experimental group
Each experiment has two parallel groups
Effects of different feeding rations on growth and IGFBP-1a and -1b gene expressions
a
fg
c
b
a
ded
cbc
ef fg fgh fgh
gh gh gh gh
Feng Q et al. unpublished data
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abcdabcd
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bcd
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abcd
abcd
abcd
a
ab
abcd
dcd
IGFBP-1a
bcd
bcd
bcde
bcde
bcd
bcde
bcde
de
abc
abcd
bcd
bcde
a
ab
cde
e
IGFBP-1b
Feng Q et al. unpublished data
Effect of diet protein levels on growth and IGFBP-1 gene expression
a
a
b
bccd
d
d ee ef
efg
efg
g
Feng et al. unpublished data
ab
cde
aaa
bcbc
bcd
bcd
cde
cdede
e
IGFBP-1a
aab
ab abab
abcabc
ababc
cdede
de e
IGFBP-1b
Feng et al. unpublished data
abcd
bcde
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aab
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bcdef
cdef
ef
eff
IGFBP-1a
abc
cd
a
ab
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cdcd
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IGFBP-1b
Feng et al. unpublished data
Conclusions and Discussion
• The hepatic IGF-I expression is under the regulation of GH and nutritional states. This dual regulation of IGF-I represents an interface between nutrients and hormones acting in concert to control animal growth.
• The GH-IGF-I axis plays central roles in fish growth regulation.
• These results suggest that the levels of IGF-1 and IGFBP-1 expression (or their ratio) are useful indicators of growth and may be useful tools in nutrient utilization and stress assessment.
• IGFs in blood and other extracellular fluids are present in complexes with several IGFBPs.
• The levels of IGFBP-1 expression is reversely correlated with growth.
• IGFBP-1 is highly induced by food deprivation, malnutrition, stress, and hypoxia.
Hypoxia followed by re-oxygenation accelerates growth and developmental rates
Catch-up growth
Kamei et al. (2011) Development
Supported by grants from:National Science FoundationNational Institutes of Health
National Heart, Lung and Blood Institute , NIH