Metabolische Programmierung durch die perinatale Zufuhr

Transcription

Metabolische Programmierung durch die perinatale Zufuhr
essentieller mehrfach ungesättigter Fettsäuren (G. Hornstra)
Inzwischen wird weithin akzeptiert, dass eine unzulängliche Ernährung in entscheidenden Phasen des perinatalen Lebens sozusagen Ereignisse «vorprogrammieren» kann, die den späteren Gesundheitszustand,
Funktionen oder Leistung beeinflussen. Die essentiellen mehrfach ungesättigten Fettsäuren (ePUFA) erfüllen
lebenswichtige Funktionen im menschlichen Körper. Diese Fettsäuren können nicht oder kaum vom Menschen
synthetisiert werden, daher ist ihre ausreichende Zufuhr von hoher funktioneller Bedeutung. Bei der Zusammenstellung der Maastricht Essential Fatty Acid Birth Cohort (MEFAB-Kohorte) zeigte sich, dass der ePUFA-Status
der Neugeborenen (der vom mütterlichen ePUFA-Konsum, Stoffwechsel und Placentatransfer abhängt) ziemlich unterschiedlich und für einen Teil der Neugeborenenpopulation möglicherweise nicht optimal ist.
Spätere Beobachtungsstudien bestätigten im Allgemeinen den positiven Zusammenhang zwischen der frühzeitigen Versorgung mit Omega-3-PUFA und der späteren geistigen Entwicklung.
Adipositas und Insulinresistenz sind grosse und noch immer zunehmende Gesundheitsprobleme, die nachweislich früh im Leben vorprogrammiert werden. Untersuchungen an der MEFAB-Kohorte haben gezeigt, dass die
Konzentrationen von gamma-Linolensäure (GLA) und/oder Dihomo-gamma-Linolensäure (DGLA), Vorstufen
der wichtigen funktionellen Omega-6-PUFA Arachidonsäure, im Nabelschnurplasma im Alter von 7 Jahren
umgekehrt mit diesen Komponenten des metabolischen Syndroms sowie den Triacylglycerol-(TAG)-Plasmakonzentrationen bei Follow-up assoziiert sind. Diese Beobachtungen könnten bedeuten, dass eine höhere mütterliche (D)GLA-Zufuhr während der Schwangerschaft möglicherweise zur Prävention des metabolischen Syndroms und seiner Komplikationen wie ischämische Herzkrankheit und Diabetes mellitus Typ 2 beitragen könnte.
Interessanterweise waren Insulinresistenz und TAG-Plasmakonzentration im Alter von 7 Jahren positiv mit den
(D)GLA-Konzentrationen bei Follow-up assoziiert. In der Tat wurden die niedrigste Insulinresistenz und die
niedrigsten TAG-Plasmakonzentrationen bei den Kindern mit einer hohen perinatalen (D)GLA-Zufuhr und einem
niedrigen (D)GLA-Status bei Follow-up beobachtet. Diese Beobachtung weist darauf hin, wie wichtig es ist, die
frühe Geschichte der Studienteilnehmer in Design und Interpretation zukünftiger Studien einzubeziehen.
La représentation de l‘alimentation dans les médias et son
influence potentielle sur les consommateurs (G. Hornstra)
Il est désormais communément admis qu’une nutrition inappropriée à des stades essentiels de la vie périnatale
peut déclencher des événements de «programmation» influençant à long terme la santé, les fonctions ou les
performances des individus.
Les acides gras polyinsaturés essentiels (AGPIe) remplissent plusieurs fonctions de première importance dans
l’organisme humain. Ces acides gras ne peuvent être synthétisés par l’homme, ou difficilement ; un apport approprié est donc indispensable au bon fonctionnement de l’organisme. Lors de la constitution de la cohorte Maastricht
Essential Fatty Acid Birth (cohorte MEFAB), il est apparu que le statut en AGPIe néonatal (qui dépend des apports
en AGPIe de la mère, du métabolisme et du transfert placentaire) est relativement variable, et peut ne pas être
optimal pour une partie de la population néonatale. Par conséquent, l’impact potentiel des différences d’exposition
périnatale aux AGPIe sur le développement du fœtus et du nourrisson constitue un axe de recherche important.
L’obésité et l’insulino-résistance sont des problèmes de santé publique majeurs, de plus en plus fréquents, dont
la programmation intervient aux premiers stades de la vie. Les études menées auprès de la cohorte MEFAB
ont démontré que les concentrations plasmatiques ombilicales d’acide gamma-linolénique (GLA) et/ou d’acide
dihomo-gamma-linolénique (DGLA), précurseurs d’un AGPIe oméga-6 jouant un rôle fonctionnel majeur, l’acide
arachidonique, sont inversement corrélées à ces composants du syndrome métabolique à l’âge de 7 ans, ainsi
qu’aux concentrations plasmatiques de triglycéride (TG) lors du suivi (6). Ces observations nous permettent de
supposer qu’un apport en (D)GLA accru pendant la grossesse pourrait contribuer à prévenir le syndrome métabolique et ses complications, telles que les cardiopathies ischémiques et le diabète de type 2.
Il est intéressant de noter que l’insulino-résistance et la concentration plasmatique de TG à l’âge de 7 ans ont été
positivement associées aux concentrations de (D)GLA lors du suivi. De fait, l’insulino-résistance la moins marquée
et les concentrations plasmatiques de TAG les plus faibles ont été observées chez les enfants qui associaient une
exposition périnatale au (D)GLA importante et un faible statut de (D)GLA lors du suivi. Il sera donc important de
tenir compte des antécédents infantiles des sujets de l’étude pour élaborer le plan des futures études et interpréter
leurs résultats.
5
Prof. Gerard Hornstra, Universität Maastricht und
NUTRI-SEARCH, Gronsveld, Niederlande
Gerard Hornstra (*1938) studierte Medizin an der Erasmus-Universität in Rotterdam und an der Staatsuniversität Leiden, wo er seinen Abschluss mit ‚cum laude‘ machte. Seine berufliche Ausbildung auf dem Gebiet der Experimentellen Ernährung absolvierte er in den Unilever Research Laboratories in Vlaardingen.
Im Jahr 1981 promovierte er an der Universität Maastricht mit einer Dissertation mit dem Titel ‚Diätetische
Fette und Arterienthrombose’ zum Dr. med.
1980 ging Prof. Hornstra an die Universität Maastricht und richtete dort eine Forschungsreihe zur Untersuchung der Relevanz der essentiellen Fettsäuren für die Gesundheit mit dem besonderen Schwerpunkt
kardiovaskuläre Erkrankung und frühe menschliche Entwicklung ein. 1995 wurde er an der gleichen
Universität zum Professor für Experimentelle Ernährung berufen. Aber auch nach seiner Pensionierung
Anfang 2003 betreut und berät Prof. Hornstra weiterhin PhD-Studenten und befasst sich mit der Untersuchung der potenziellen Bedeutung essenzieller mehrfach ungesättigter Fettsäuren für die Programmierung
der menschlichen Entwicklung. Ausserdem ist er als privater Berater auf dem Gebiet ‚Nahrungsfette in Gesundheit und Krankheit’ tätig. Prof. Hornstra ist Vorsitzender des niederländischen Arbeitskreises ‘Choose
Healthy Fats / Wähle gesunde Fette’ und Mitglied des Lenkungsausschusses des International Expert
Movement on Health Significance of Fat Quality of the Diet.
Prof. Gerard Hornstra, Université de Maastricht et
NUTRI-SEARCH, Gronsveld, Pays-Bas
Gerard Hornstra (*1938) a poursuivi ses études de médecine à l’université Erasmus de Rotterdam, ainsi
qu’à l’université d’État de Leiden, où il obtient son diplôme avec distinction. C’est ensuite dans le domaine
de la nutrition expérimentale qu’il acquiert son expérience professionnelle, dans les laboratoires de recherche Unilever à Vlaardingen. En 1981, Gerard Hornstra obtient son doctorat de médecine à l’université
de Maastricht, après avoir soutenu avec succès une thèse intitulée Dietary fats and arterial thrombosis.
En 1980, le Prof. Hornstra rejoint l’université de Maastricht, où il initie des travaux de recherche sur les
effets sur la santé des acides gras essentiels, spécifiquement axés sur les maladies cardiovasculaires et
les premières années de la vie. En 1995, il est nommé professeur de nutrition expérimentale dans cette
même université. Depuis son départ à la retraite, début 2003, le Prof. Hornstra continue de superviser et
conseiller les doctorants, et d’étudier l’importance potentielle des acides gras polyinsaturés essentiels dans
la programmation du développement de l’être humain. Il exerce par ailleurs en tant que consultant dans
le domaine des lipides alimentaires et leur effet sur la santé et la morbidité. Le Prof. Hornstra préside le
groupe de travail néerlandais Kies Gezond Vet (Choisir les bonnes matières grasses), et siège au comité
directeur de l’International Expert Movement on Health Significance of Fat Quality of the Diet.
6
SGE, Bern
120709
Nutritional programming by perinatal
essential polyunsaturated fatty acids
Programming by perinatal essential
polyunsaturated fatty acids
 Introduction
Gerard Hornstra PhD
 Birth weight
Prof. Em. of Experimental Nutrition
Maastricht University
and
NUTRI-SEARCH
Gronsveld, the Netherlands
 Brain development
 Metabolic syndrome
 Summary and
implications
© NUTRI-SEARCH 2012
Essential polyunsaturated fatty acids (ePUFA)
Nutritional programming
 ‘Programming’
’ occurs when an early stimulus,
operating at a critical or sensitive period,
results in a permanent or long-term change in
the structure or function of the organism
(Lucas, 1991)
 Essential fatty acids (EFA) and their longer-chain,
more-unsaturated derivatives (LCPUFA) are
collectively called essential polyunsaturated fatty
acids (ePUFA)
 Inadequate nutrition during fetal- or early life
may act as a programming event and, thereby,
may permanently affect later health, function, or
achievement in man
(Dobbing, 1981)
 These fatty acids serve vital functions in the human
body, but cannot (EFA) or hardly (LCPUFA) be
produced in the human body
 There are two ePUFA families, the omega-6 and
omega-3 families
 Therefore, their adequate dietary intake is essential
for optimal health
Arachidonic acid (ARA) and docosahexaenoic acid
(DHA) are the most important functional LCPUFA
ARA (omega-6)
DHA (omega-3)
 growth
 brain function
 metabolic control
 neuro-motor control
 gene expression
 visual performance
 inflammation
 gene expression
 thrombosis
 ARA modulation
Programming by breastfeeding
 Compared to formula feeding, breastfeeding has
been shown to be associated with health benefits in
later life (e.g. less obesity, improved mental
development, lower cardiovascular risk, etc.)
 Multiple factors, genetic, psychological as well as
compositional, are considered of importance in this
association
 One of the compositional factors may be the
difference in ePUFA concentrations: formula is rich
in EFA, breast milk contains larger amounts of a
variety of omega-6 and omega-3 LCPUFA
[email protected]
7
SGE, Bern
120709
The Maastricht Essential Fatty Acid
Birth (MEFAB) cohort
The neonatal LCPUFA status is quite variable
(MEFAB database, n=1016)
300
To investigate whether the
early availability of LCPUFA
DHA
200
200
(as indicated by their
150
150
concentrations in maternal
100
100
and cord PL) may be
involved in programming
pregnancy outcome and/or
50
50
0
0
child development
LCPUFA concentration (%) in cord plasma phospholipids
Programming of birth weight
 Low birth weight is a reliable risk indicator for later health
problems because it is associated with higher risks of
chronic diseases, like cardiovascular disease and type 2
diabetes
 Introduction
 The underlying mechanism may include higher catch-up
growth, resulting in unfavorable programming effects of
metabolic stress
 Birth weight
 Summary and
implications
GA-16
3250
3200
3200
3150
3150
3100
3100
IV
V
I
II
III
IV
V
Birth weight (g)
3250
3400
4
2
5
3
3000
1
2600
300
DHA (ln, quintiles)
DHA (ln, quintiles)
6
3350
3300
III
(r=0.62; n=755; p<0.0001)
3800
B=-12.6; n=467; p=0.578 (NS)
3300
II
Birth weight is positively related to placental weight
Delivery
B=62.0; n=473; p=0.001
I
 Further studies point to omega-3 LCPUFA as the active
principle
©
Birth weight is positively related to maternal plasma DHA
concentrations at early pregnancy only (Dirix, 2008)
3350
 Observational studies suggest that maternal fish intake
during pregnancy promotes fetal growth, thereby reducing
the stimulus for catch-up growth
 However, results of observational and intervention studies
are not consistent
NUTRI-SEARCH 2012
Birth weight (g)
250
ARA
250
400
500
Placental weight (g)
600
700
© NUTRI-SEARCH
2012
[email protected]
8
SGE, Bern
120709
Placental weight is positively related to maternal plasma
DHA concentrations at early pregnancy only
at delivery
at 16th pregn. week
Placental weight (g)
510
B=44.5; n=797; p=0.010
B=-21.4; n=833; p=0.245 (NS)
510
500
500
490
490
480
480
470
470
460
I
II
III
IV
V
I
DHA (ln, quintiles)
II
III
IV
V
460
 Fetal growth, corrected for gestational age, is
positively associated with the maternal DHA status
early in pregnancy only
 This putative programming effect of DHA on fetal
growth may be mediated by a stimulating influence of
DHA on placental development
 Interestingly, in most intervention studies so far,
maternal supplementation with DHA did not promote
fetal growth corrected for gestational age
 However, supplementation usually started around
mid-pregnancy, which may have been too late to
initiate a placenta-mediated programming response
Programming of brain function by prenatal
LCPUFA availability?
polyunsaturated fatty acids (ePUFA)
 Introduction
 Summary and
implications
 Brain development mainly takes place during late
gestation and early extra-uterine life
 The perinatal LCPUFA is quite variable (ARA: 10-20%,
DHA: 3-10%)
 Does this difference in perinatal LCPUFA availability affect
later brain function, mental and visual development, and
child behavior?
Brain development, as reflected by movement quality at 7
years of age, is positively related to DHA status at birth
(n=290; Bakker, 2009)
p=0.287
120
Maastricht Motor Test
(mean adjusted score)
100
75
50
25
0
 Certain LCPUFA are important ‘building bricks’
’ of the
brain
Cognitive performance at 7 years of age is not related
to DHA status at birth (n=305; Bakker, 2003)
125
 Breast feeding has been shown to be associated with later
mental and visual benefits compared to formula feeding
 In contrast to the formula of that time, breast milk contains
LCPUFA
 Birth weight
Kaufman MPC
(mean adjusted score)
Programming of fetal growth by DHA
4.3
5.5
6.5
7.9
Umbilical plasma DHA quartiles (%)
p=0.010
110
100
90
4.3
5.5
6.5
7.9
Cord plasma DHA quartiles (%)
[email protected]
9
SGE, Bern
120709
120
1.2
p=0.038
p=0.022
VEP P100 latency
(adjusted mean, msec)
visual acuity
(adjusted mean)
Speed of visual information processing at 8 years of age is
higher, the higher the DHA status at birth (n=33)
110
1.0
100
0.8
90
0.6
1
4.3
5.5
6.5
7.9
Cord plasma DHA quartiles (%)
problem score
52.5
50.0
47.5
45.0
The Child Behavior Check List
is a standardized parent-report
instrument for the assessment
of behavioral and emotional
characteristics of children
Internalizing behavior
 somatic complaints
4.3
5.5
6.5
7.9
Quartiles of cord plasma DHA (%)
16
14
12
10
4
1
2
3
4
Internalizing behavior (CBCL) of formula-fed children
at age 7 is less problematic, the higher their
DHA status at birth (n = 215; Krabbendam 2007)
p=0.002
3
p=0.037
Umbilical plasma DHA quartiles (%)
55.0
2
18
ERG a-wave latency
(adjusted mean, msec)
Brain maturation, as reflected by visual acuity at 8 years
of age, is positively related to DHA status at birth (n=59)
 anxious/depressed
 withdrawal
Programming of brain development by DHA-1
 In MEFAB, prenatal exposition to DHA is positively associated
with various aspects of brain function later in life (e.g. visual
functions, cognition, behavior, etc.)
 None of the outcome measures correlated significantly with
the DHA status at 7 years of age
 This suggests that for certain aspects of brain development,
programming by prenatal DHA availability is more important
than the DHA availability in later life
 This may be the reason why supplementation of term infants
with DHA hardly improves their mental and visual
development
Programming of brain development by DHA-2
 A positive relationship between omega-3 LCPUFA
consumption of mothers during pregnancy and later mental
and visual development of their children has repeatedly
been observed in large cohort studies
 However, maternal supplementation during pregnancy with
DHA or fish oil did hardly benefit later selected brain
functions of their infants
 Since supplementation usually started around midpregnancy, this may have been too late to initiate a
successful programming response
 Introduction
 Birth weight
 Summary and
implications
[email protected]
10
SGE, Bern
120709
Programming of metabolic syndrome
by LCPUFA?
 Compared to formula-feeding, breastfeeding reduces the risk
of later obesity, hypertension, and diabetes type 2, all
components of the metabolic syndrome
 Among the many factors possibly involved, the difference in
fatty acid composition between human milk and formula may
be of importance
 Formula are rich in linoleic- and alpha-linolenic acids, but only
current formula contain ARA and DHA
 However, most formula are devoid of other omega-6 and
omega-3 fatty LCPUFA, present in human milk
1.4
Body fatness
(leptin,µ
µg/L)
4.5
P = 0.047
Insulin resistance
(HOMA index)
1.4
P = 0.011
4.0
1.2
0.5
3.5
1.0
0.4
3.0
0.8
0.3
2.5
low medium high
0.6
low medium high
< 0.04
> 0.07
Plasma TG
(mmol/L)
0.6
0.2
P = 0.045
low medium high
Insulin resistance (HOMA) at follow-up (age 7) is
negatively related to the GLA status at birth and
positively to the GLA status at follow-up
Plasma TG (mmol/L) at follow-up (age 7) is negatively
related to the DGLA status at birth and positively
to the DGLA status at follow-up
GLA at birth (%)
1.4
1.2
1.2
1.0
0.8
low
(< 0.04)
middle
GLA at follow up (%)
0.60
P = 0.000
P = 0.011
0.6
Plasma GLA content (%) at birth may predict later risk
of metabolic syndrome (Rump, 2002)
0.60
P = 0.001
0.50
0.55
1.0
0.40
0.50
0.8
0.30
0.45
0.6
high
DGLA at birth (%)
(> 0.07)
low
(< 0.06)
middle
high
(> 0.10)
0.20
DGLA at follow-up (%)
P = 0.034
0.40
low
(< 4.83)
middle
high
low
(> 5.46)
(< 2.68)
middle
high
(> 3.16)
© NUTRI-SEARCH
© NUTRI-SEARCH
Programming of postnatal health aspects
by prenatal GLA and DGLA status
2012
2012
 In MEFAB children, a higher prenatal availability of
gamma-linolenic and/or dihomo-gamma-linolenic acid
availability was associated with reduced levels of
certain components of the metabolic syndrome (plasma
TG, insulin resistance, body fatness) at 7 years of age
 This observation implies that prevention of the
metabolic syndrome and its complications may be
supported by a higher maternal intake of gammalinolenic acid during pregnancy
 Postnatal (D)GLA supplementation, however, seems
contra-indicated, but more research is needed
 Introduction
 Birth weight
 Summary and
implications
[email protected]
11
SGE, Bern
120709
Programming by perinatal LCPUFA:
Summary
Programming by perinatal LCPUFA:
methodological implications for further research
 It is now widely accepted that nutrition during pre- and early
post-natal life can program long-term health, and is involved
in the risk of certain chronic diseases later in life
 Intervention studies, required to proof causality of
associations, are of limited duration, whereas results of
cohort studies relate to life-long dietary exposure
 Early exposition of the developing fetus to certain LCPUFA
is positively associated with birth weight (DHA), and with
certain aspects of brain development (DHA) and of the
metabolic syndrome (DGLA) at childhood
 In addition, most intervention studies may have started too
late in pregnancy to initiate early programming effects
 If causal, these associations imply that supplementation of
pregnant women with these fatty acids could support the
longer-term development and health of their offspring
 However, intervention studies with DHA during pregnancy
mainly failed to confirm the promising results of
observational studies
 Therefore, future intervention studies should start early in
pregnancy or preferably before conception
 Whenever possible, design and interpretation of postnatal
intervention studies should take into account potential
programming-associated response differences
 Notwithstanding the problem of residual confounding, cohort
studies remain of essential importance in nutrition research
Nutritional programming by perinatal
essential polyunsaturated fatty acids
For further information
on the MEFAB cohort,
please contact
G. [email protected]
[email protected]
12

Metabolische Programmierung durch die perinatale Zufuhr

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