Early Life Origins of Obesity: Role of Hypothalamic...
Transcript of Early Life Origins of Obesity: Role of Hypothalamic...
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
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
ObesityDiabetes
Cardiovascular Risks
Perinatal Food RestrictionPerinatal OverfeedingCatch-up Growth
Early Growth and Later Risk of Diabesity in Humans
Key Role for the Brain in Body Weight Regulation
Reeves, 1969
Hetherington and Ranson, 1940
Hypothalamic Circuits Involved in Appetite Regulation
MCHOX
Bouret,JPGN, 2009
Critical Periods for Hypothalamic Development
?
from Bouret, Forum Nutr, 2010
“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
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
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
Method to Study Development of Hypothalamic Feeding Circuits
ARH
DiI
adapted from, www.hhmi.org “Science of Fat”
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
Secretion Pattern of Peripheral Signals inPostnatally Under- and Over-Nourished Animals
ChemokinesCytokines
Metabolic Hormones
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
Leptin Deficiency and Hypothalamic Neural Projections
+ / + ob/obP10 P10
PVH PVH
+ / + ob/obAdult Adult
PVH PVH
+/+ 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
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
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 ?
Programming Actions of Ghrelin on MetabolismPre-Weaning Growth Curve Post-Weaning Growth Curve
Adult GlycemiaAdult Food Intake
Long-Term Effects of Postnatal Ghrelin Blockade on Adiposity
Control Anti-Ghrelin
perirenal
visceralsubcutaneous
Postnatal Ghrelin Blockade Increases ARH Neural Projections
Control Anti-GhrelinP12 P12
PVH PVH
Conclusion I
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
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