early life origins of obesity: role of hypothalamic...
TRANSCRIPT
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BCYF Symposium(05/2010)
Early Life Origins of Obesity:
Role of Hypothalamic Programming
Sebastien G. Bouret, Ph.D.
The Saban Research InstituteChildrens Hospital of Los AngelesUniversity of Southern California
USC Keck School of MedicineLos Angeles, CA - USA
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A Striking Example of Environmental Control Phenotypic Polymorphism
weight (x2)longevity (x20)
fertility
Queen
Worker
Honey bee larvae with identical DNA
Royal Jelly
Worker Food
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ObesityDiabetes
Cardiovascular Risks
Perinatal Food RestrictionPerinatal OverfeedingCatch-up Growth
Early Growth and Later Risk of Diabesity in Humans
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Key Role for the Brain in Body Weight Regulation
Reeves, 1969
Hetherington and Ranson, 1940
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Hypothalamic Circuits Involved in Appetite Regulation
MCHOX
Bouret,JPGN, 2009
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Critical Periods for Hypothalamic Development
?
from Bouret, Forum Nutr, 2010
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“Bedside to Bench”: Animal Models of Postnatal Over- and Under-nutrition
• Mechanistic studies can easily be done in animal models
• Brain feeding pathways are highly conserved during evolution
• Studies in the human hypothalamus have been limited in part by instrument resolution
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Normal Litter (7)
Mouse Model of Postnatal Over- and Under-nutrition :Divergent Litter Size
Large Litter
Normal Litter
Small Litter
Large Litter (14) undernourished
Small Litter (3) overnourished
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Adult Growth of Neonatally Under- and Over-Nourished Animals
SL
NLLL
Normal Litter (7)
Large Litter (14) undernourished
Small Litter (3) overnourished
P4-P22
SL
b
aa
NL LL
Catch-Up Growth
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Method to Study Development of Hypothalamic Feeding Circuits
ARH
DiI
adapted from, www.hhmi.org “Science of Fat”
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Impact of Early Postnatal Nutrition on Formation of Hypothalamic Neural Projections
SL NL LL
b
a
b
PVH
V3
Underfed (LL) P12
PVH
Overfed (SL) P12
V3
PVH
V3
Normal Fed P12
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Secretion Pattern of Peripheral Signals inPostnatally Under- and Over-Nourished Animals
ChemokinesCytokines
Metabolic Hormones
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Is Leptin a Signal for Hypothalamic Development ?
LeptinRel
ativ
e Le
vels
Postnatal Age (weeks)
Weaning Puberty
1 2 3 4
Body
Wei
ght
(g)
Postnatal Age (days)7 8 9 10
0
2
4
6
Leptin
Vehicle
11
Caron et al., J Comp Neurol, 2010
Leptin-induced pSTAT3 P10
ARHV3
me
Leptin Receptor mRNA P10
ARH
me
V3
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Leptin Deficiency and Hypothalamic Neural Projections
+ / + ob/obP10 P10
PVH PVH
+ / + ob/obAdult Adult
PVH PVH
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+/+ ob/ob
V3 V3
ob/ob + leptin
V3
0
5
10
15
20
25
30
0
5
10
15
20
25
30
WT ob/ob ob/ob+
Leptin
PVH
**
AgRP Fiber Density
PVH
PVH
PVH
Adult Treatment
Leptin Acts during a Neonatal Critical Period to Induce its Neurodevelopmental Effects
Neonatal Treatment
ob/ob
PVH PVH
ob/ob + leptin
PVH
DiI Fiber Density
+/+
Bouret et al., Science, 2004
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Postnatal Secretion of Metabolic Hormones
Ghrelin
LeptinRel
ativ
e Le
vels
Postnatal Age (weeks)
Weaning Puberty
1 2 3 4
?
adapted from Grove and Cowley, 2005
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2
The answer to this latter problem was solved by the discovery and develop-
ment of Spiegelmers (Klussmann et al., 1996; Vater & Klussmann, 2003).
These molecules, which are biostable aptamers, have all of the diversity char-
acteristics of aptamers but possess a structure that prevents enzymatic degra-
dation.
2) Identification of Spiegelmer Products
While aptamers are created from the natural D-nucleotides, which are recog-
nized by the nucleic acid degrading enzymes, a molecule synthesized as the
mirror image L-oligonucleotide will not be degraded by any nucleases since
there are no such enzymes in the body capable of interacting with these un-
natural molecules. As such, the amplification methods used to create large ap-
tamer libraries cannot be employed to synthesize the L-nucleic acid-containing
molecules. However, NOXXON has developed the methods to form high affin-
ity L-oligonucleotide aptamers that possess outstanding binding affinities and
functionality. These molecules are termed “Spiegelmer” from the German
“Spiegel” or mirror.
Figure 1.1 Reciprocal specificities of (D-) aptamers and (L-) Spiegelmers
aptamer •••• naturaltarget
mirror-image •••• mirror-imagetarget aptamer
mirror-image •••• aptamertarget
Spiegelmer •••• naturaltarget
P4-P21
NOX B-11 (SPM) Ghrelin
P4 P21 Adult
birth weaning
Ghrelin Ghrelin
Does Ghrelin Act on Hypothalamic/Metabolic Programming ?
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Programming Actions of Ghrelin on MetabolismPre-Weaning Growth Curve Post-Weaning Growth Curve
Adult GlycemiaAdult Food Intake
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Long-Term Effects of Postnatal Ghrelin Blockade on Adiposity
Control Anti-Ghrelin
perirenal
visceralsubcutaneous
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Postnatal Ghrelin Blockade Increases ARH Neural Projections
Control Anti-GhrelinP12 P12
PVH PVH
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Conclusion I
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Perinatal Levels of Metabolic Hormones / Perinatal Nutrition
Low High
High
Low
Optimal
Rel
ativ
e R
isk
of D
evel
opm
ent
of M
etab
olic
Dis
ease
in
Adu
lt Li
fe
Abnormal
Optimal
Hyp
otha
lam
ic
Dev
elop
men
t
Conclusion II: Adverse Perinatal Nutritional and Hormonal Environments Increase
the Susceptibility to Adult Metabolic Disease
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Postnatal Exposure Adult Exposure
Adapted from Shearman et al., 2006
Conclusion III: Hormonal Programming: Timing is Important!
It is important to determine when key developmental events are particularly sensitive to hormonal signals during restricted ontogenetic periods
Steculorum and Bouret, unpublished