1. Nutritional programming
Theories
Dr Yousef M. Elshrek

2. • The environment encountered‫ يواجه‬in fetal and
neonatal life exerts ‫ يبدل‬a profound influence on
physiological function and risk of disease in
adult life.
• Epidemiological evidence suggests that
impaired fetal growth followed by rapid catch-
up in infancy is a strong predictor of obesity,
hypertension, non-insulin-dependent diabetes
and CHD.
• Whilst these associations have been widely
accepted to be the product of nutritional factors
operating in pregnancy, evidence from human
populations to support this assertion is scarce.

3. • Animal studies clearly demonstrate that
there is a direct association between
nutrient imbalance in fetal life and later
disease states, including hypertension,
diabetes, obesity ,CHD and renal
disease.
• These associations are independent of
changes in fetal growth rates.
• Experimental studies examining the
impact of micro- or macronutrient
restriction and excess in rodent
pregnancy provide clues to the
mechanisms that link fetal nutrition to
permanent physiological changes that
promote disease.

4. • Exposure to glucocorticoids (Any of a
group of steroid hormones, such as
cortisone, that are produced by the
adrenal cortex, are involved in
carbohydrate, protein, and fat metabolism,
and have anti-inflammatory properties ) in
early life appears to be an important
consequence of nutrient imbalance
and may lead to alterations in gene
expression that have major effects on
tissue development and function.

5. The early-life origins of health and
disease
• Epigenetic mechanisms, including DNA methylation,
may also be important processes in early-life
programming.
• The environment encountered during fetal
life and infancy appears to be strongly
related to risk of non-communicable
diseases in adult life (Barker 2004).
• In order to explain these apparently causal
relationships it is proposed that adaptations
during critical phases of growth and
development may ensure the maintenance of
homeostasis, and hence survival, when the
environment is compromised.

6. • Variation in nutrient supply during early
development appears to be a strong
signal initiating these adaptive processes
• The means through which events in early
life trigger permanent responses have
been described as nutritional or metabolic
programming (Lucas, 1991).
• These terms describe the process
through which a stimulus or insult during
a critical window of fetal or infant
development elicits ‫ يستنبط‬permanent
responses that produce long-term
changes in tissue structure or function.

7. • Programming is the consequence of
the innate capacity of developing
tissues to adapt to the conditions that
prevail during early life, which for
almost all cell types in all organs is an
ability that is present for only a short
period before the time of birth.
• The epidemiological studies that first
indicated that disease could be
programmed by intrauterine influences
formed the basis of what became
known as the ‘fetal origins of adult
disease hypothesis’, or the ‘Barker
hypothesis’.

8. • This constantly evolving concept is
now described as the developmental
origins of health and disease
hypothesis.
• The developmental origins of health
and disease hypothesis was originally
developed to explain associations
between patterns of fetal and infant
growth and major disease states in
human populations, but has received
strong support from experimental
studies in animals.

9. Clues from epidemiology
• The first clues that the environment
encountered in early life could determine risk
of disease in adulthood came from
ecological studies evaluating the causes of
the north-south divide in disease patterns in
England and Wales (Barker and Osmond,
1986)
• These studies identified the period around
the time of birth as playing a critical role in
the development of CHD (Osmond et al ,
1990).

10. • Low weight at birth is associated with
increased risk of CHD mortality, raised
adult blood pressure), non-insulin-
dependent diabetes and risk of the
metabolic syndrome.

11. • The birth weight-disease associations
have been confirmed in a large number of
independent cohorts all around the
developed and developing world.
• Based on fairly limited evidence the
association has been attributed to the
impact of a poor plane of nutrition before
and during pregnancy (see Fig 1).

12. • Fig. 1 Schematic representation of the Barker hypothesis.
• The simplest form of the hypothesis is that undernutrition impairs fetal
growth.
• The association between fetal growth and long-term disease outcomes is
likely to be confounded by a direct association between undernutrition and
disease.

13. Life-course perspectives on
health and disease
• The aetiology of non-communicable
disease is invariably complex, and is now
regarded as involving influences at all
stages of the life-course, a concept best
considered using the example of CHD.
• It is long-established that CHD is usually
related to adult environmental and lifestyle
factors, including a high-fat diet, poor
dietary antioxidant status and smoking.

14. • These environmental factors are
clearly not the only determinants
of risk, as the individual genotype
determines the impact of dietary
risk factors.
• In other words, the adult risk of
disease is related to a ‘phenotype’
that is defined by interaction
between the genotype and the
environment.

15. • This adult phenotype is, however, also
shaped by nutrient-gene interactions in
adolescence, in childhood, infancy and
in fetal life
• Thus, early-life programming is just
one facet of the way in which
adaptations to insults or stimuli at
different life stages determine the adult
physiology and metabolic profile and
the responsiveness of the individual to
metabolic or endocrine ‫افراز هرمون‬
‫داخلي‬signals.

16. Nutritional programming
concept
• Nutritional programming in utero affects the
incidence and severity of disease in the
adult.
• This hypothesis has established a
relationship between nutritional
environment during critical windows of
development plasticity and offspring
disease in adult life. Or
• In 1992 Hales and Barker proposed a new
hypothesis concerning the causes and
origins of type 2 diabetes, emphasizing the
nutritional conditions in early life

17. • Their ‘‘thrifty phenotype’’
hypothesis suggests that during
gestation and early postnatal life
an individual becomes
programmed for nutritional thrift in
order to adapt to and survive in an
environment of limited resources
and poor nutrition.

18. • Once established, this acquired
metabolic phenotype is maintained
throughout the lifetime of the
individual, and does not change
• The nutritional programming concept
derives from two prior hypotheses:
1. the Thrifty Phenotype or Barker Fetal
Origins of Disease hypothesis (Barker,
1997) and
2. the extended ‘Predictive Adaptive
Response’ (PAR) hypothesis
(Gluckman & Hanson, 2004).

19. •Fig. 2 The thrifty phenotype hypothesis

20. • The thrifty phenotype hypothesis
• Exposure of the developing
organism to a low plane of
nutrition promotes metabolic thrift
in order to ensure survival.
• In a postnatal environment in
which nutrients are in short supply
this metabolic thrift continues to
be a survival trait, but if nutrients
are present in excess the thrifty
trait will promote the metabolic
syndrome

21. The Thrifty Phenotype
hypothesis
• The Thrifty Phenotype hypothesis
proposed that in utero undernourishment
results in permanent detrimental changes
leading to the development of diseases
later in life.
• The effects of maternal under-nutrition on
fetal development has been studied
extensively both in humans and
experimental animals.

22. • The initial evidence was based on
epidemiological studies of survivors of
the Dutch famine of 1944–1945, where
perinatal exposure to famine conditions
resulted in higher prevalence of
overweight in adult offspring.
• Subsequent studies showed that
perinatal nutritional deficiencies
predispose adult offspring to metabolic
syndrome, including obesity,
cardiovascular disease (CVD),
hypertension, and type 2 diabetes

23. The Predictive Adaptive
Response (PAR) hypothesis
• The Predictive Adaptive Response (PAR)
hypothesis proposes that the fetus makes
adaptations based on the predicted postnatal
environment.
• The prenatal nutritional environment is the
primary source of ‘prediction’ of the
environment available to the fetus per this
hypothesis.
• When the PAR is appropriate, the phenotype
is normal;

24. • however, when there is a mismatch
between the nutritional environment,
either high or low, during critical
developmental periods and the adult
environment, disease will develop.
• PARs can only be induced during
critical windows of development.
• Thus, the windows of potential
induction differ for different organs,
resulting in extension of the plasticity
phase from in-utero to post-natal
development.

25. • Furthermore, PAR also extended
Bakers hypothesis to nutritional
mismatch both to under-nutrition and
over-nutrition during critical
developmental periods
• Whether adaptive or predictive,
developmental programming postulates
long-term detrimental effects on adult health
due to nutritional imprinting during critical
developmental periods.
• Understanding and mapping the interaction
between nutrient imbalance and modification
of gene expression have an enormous
potential for improving the health of future
generations

26. What is the direction?
• Nutritional programming research
requires the multi-disciplinary
approach of nutritional genomics in
relying on the concepts and
technologies of genetics, molecular
biology, epidemiology, public health
and clinical trials.
• Model systems based on rodents and
mammalians are indispensable, and
provide valuable insights into
molecular mechanisms underlying
nutritional programming.

27. • Additionally, more studies are
required to reach a better
understanding of the precise type,
timing and duration of
inappropriate nutrition that result
in chronic disease outcome.
• Significantly less data exists
regarding longer effects of
nutritional programming,
especially in human studies

28. • Although the original field of nutritional
programming focused mainly on
metabolic syndrome related diseases,
as reflected in changes in body size,
focus on detrimental effect of
unbalanced nutrition on chronic
diseases should be widened to studies
of different tissues and diseases.
• Finally, extension of studies of
nutritional programming in the pre-
conception period should be further
investigated.

29. Specific areas of interest
• Studies of the mechanism and nutrient-
gene interactions through which
nutritional programming influences
various tissues.
• Narrowing and defining critical periods
in fetal and early post-natal life that
affect specific chronic diseases.
• Identify and study the impact of genetic
determinants on early programming
effects and on subsequent outcome.

30. • Quantify the effects of early
programming on later chronic
diseases.
• Specifying the role of specific
nutrients and their interactions in
the maternal and infant diet on
programming effects on disease
and their risk factors.
• Studies of epigenetic mechanisms
in early-life programming

31. What is known about nutrition and genes
involved in nutritional programming?
• Little is known about the genes involved in
the underlying mechanism of programmed
nutrition.
• Furthermore, products of several genes
associated with a specific mechanism can
interact with other gene products in different
pathways;
• thus, studies of genes involved in nutritional
programming can reach extreme complexity.

32. • Several recent studies have begun
elucidating genes influenced by
programmed nutrition in several tissues
/ pathways, including the placenta,
endocrine pancreas, TH-receptor
pathway, renin-angiotensin system (as
related to hypertension) and adipose
tissue.
• However, this field is only beginning to
unravel genes and molecular
mechanisms involved in nutritional
programming.