Nutritional programming

Theories

Dr Yousef M. Elshrek

• The environment encounteredيواجه in fetal and neonatal life exerts يبدل a 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.

• 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.

• 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.

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.

• 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 يستنبط permanent responses that produce long-term changes in tissue structure or function.

• 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’.

• 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.

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).

• 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.

• 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).

• 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.

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.

• 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.

• 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

.signalsداخلي

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

• 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.

• 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).

•Fig. 2 The thrifty phenotype hypothesis

• 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

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.

• 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

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;

• 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.

• 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

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.

• 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

• 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.

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.

• 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

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.

• 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.