Thrifty phenotype refers to the correlation between low birth weight of neonates and the increased risk of developing metabolic syndromes later in life, including type 2 diabetes and cardiovascular diseases.Although early life undernutrition is thought to be the key driving factor to the hypothesis, other environmental factors have been explored for their role in susceptibility, such as physical inactivity. Genes may also play a role in susceptibility of these diseases, as they may make individuals predisposed to factors that lead to increased disease risk.
The term thrifty phenotype was first coined by Charles Nicholas Hales and David Barker in a study published in 1992.In their study, the authors reviewed the literature up to and addressed five central questions regarding role of different factors in type 2 diabetes on which they based their hypothesis. These questions included the following:
From the review of the existing literature, they posited that poor nutritional status in fetal and early neonatal stages could hamper the development and proper functioning of the pancreatic beta cells by impacting structural features of islet anatomy, which could consequently make the individual more susceptible to the development of type 2 diabetes in later life. However, they did not exclude other causal factors such as obesity, ageing and physical inactivity as determining factors of type 2 diabetes.
In a later study, Barker et al.analyzed living patient data from Hertfordshire, UK, and found that men in their sixties having low birthweight (2.95 kg or less) were 10 times more likely to develop syndrome X (type 2 diabetes, hypertension and hyperlipidemia) than men of the same age whose birthweight was 4.31 kg or more. This statistical correlation was independent of the gestation period and other possible confounding factors such as current social class or social class at birth, smoking, and consumption of alcohol. Furthermore, they argued that they were likely to underestimate this association, since they could only sample the surviving patients, and patients having more severe manifestations of syndrome X were less likely to survive to that age.
In 1994, Phillips’ et al.found statistically significant association between thinness in birth (measured as Ponderal index) and insulin resistance, the association being independent of length of gestation period, adult body mass index, and confounding factors like then-current social class or social class at birth.
In 2001, Hales and Barkerupdated the hypothesis by positing that the thrifty phenotype may be an evolutionary adaptation: the thrifty phenotype responds to fetal malnutrition by selectively preserving more vital organs of the body and preparing the fetus for a postnatal environment where resources will be scarce.
Maternal nutrition can affect the development of the unborn child in poor nutritional environments such that it will be prepared for survival within that poor environment. This results in a thrifty phenotype (Hales & Barker, 1992). It is sometimes called Barker's hypothesis, after Professor David J. P. Barker, researching at the University of Southampton who published the theory in 1990.
The thrifty phenotype hypothesis says that early-life metabolic adaptations help in survival of the organism by selecting an appropriate trajectory of growth in response to environmental cues. An example of this is type 2 diabetes. In their review, Barker and Hales discuss evidence that beta cells abnormally develop due to malnutrition during fetal development, causing insulin abnormalities later in life. The review also notes that low birth weight alone does not necessarily mean that it is a manifestation of thrifty phenotype. Since low birth weight is not exclusively caused by maternal malnutrition, meaning that other factors could influence the low birth weight–disease relationship.
Before the term thrifty phenotype was coined, Barker had noted the phenomenon with cardiovascular disease. In his lecture paper, he discusses the role of malnutrition during fetal development in obstructed lung disease (now known as chronic obstructive pulmonary disease [COPD]), ischemic heart disease, and blood pressure. In each of these diseases, there was an association with social class and development prevalence of the disease. This was determined to be due to issues of malnutrition during key points in organ development in utero.
However, environmental changes during early development may result in the selected trajectory becoming inappropriate, resulting in adverse effects on health. This paradox generates doubts about whether the thrifty phenotype is adaptive for human offspring. Thus, the thrifty phenotype should be considered as the capacity of all offspring to respond to environmental cues during early ontogenetic development. It has been suggested that the thrifty phenotype is the consequence of three unlike adaptive processes: maternal effects, niche construction and developmental plasticity, which all are influenced by the brain. While developmental plasticity demonstrates an adaptation by the offspring, niche construction and parental effects are result of parental selections rather than offspring fitness. Therefore, the thrifty phenotype can be described as a manipulation of offspring phenotype for the benefit of maternal fitness. The information that enters offspring phenotype during early development mirror the mother's own developmental experience and the quality of the environment during her own maturation rather than predicting the possible future environment of the offspring
Not all research into this topic has been conducted on diseases. Other research has explored the thrifty phenotype hypothesis as a causal factor for differing development into puberty and adulthood. A review on the literature, up to 2013, discussed not only the hierarchical tissue preservation within pancreatic cells, but research on limb shortening to preserve development of more vital organs and bones.An example of this phenomenon is a study published in 2018 by the Royal Society, which found that hypoxic stress from differing altitudes affected offspring limb length. Fetal overnutrition may also play a key role in development, increasing the likelihood of early puberty and obesity.
Many human diseases in adulthood are related to growth patterns during early life, determining early-life nutrition as the underlying mechanism. Individuals with a thrifty phenotype will have "a smaller body size, a lowered metabolic rate and a reduced level of behavioral activity… adaptations to an environment that is chronically short of food" (Bateson & Martin, 1999). Those with a thrifty phenotype who actually develop in an affluent environment may be more prone to metabolic disorders, such as obesity and type II diabetes, whereas those who have received a positive maternal forecast will be adapted to good conditions and therefore better able to cope with rich diets. This idea (Barker, 1992 ) is now widely (if not universally) accepted and is a source of concern for societies undergoing a transition from sparse to better nutrition (Robinson, 2001 ).
Risk factors of thrifty phenotype include advanced maternal age and placental insufficiency.
The ability to conserve, acquire and expend energy is believed to be an innate, ancient trait that is embedded in the genome in a way that is quite protected against mutations.These changes are also believed to possibly be inherited across generations. Leptin has been identified as a possible gene for the acquisition of these thrifty traits.
On a larger anatomic scale, the molecular mechanisms are broadly caused by a suboptimal environment in the reproductive tract or maternal physiological adaptations to pregnancy.
Insulin resistance (IR) is a pathological condition in which cells either fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia.
Intrauterine growth restriction (IUGR), or fetal growth restriction, refers to poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's birth weight percentile. The causes of IUGR are broad and may involve maternal, fetal, or placental complications.
A maternal effect is a situation where the phenotype of an organism is determined not only by the environment it experiences and its genotype, but also by the environment and genotype of its mother. In genetics, maternal effects occur when an organism shows the phenotype expected from the genotype of the mother, irrespective of its own genotype, often due to the mother supplying messenger RNA or proteins to the egg. Maternal effects can also be caused by the maternal environment independent of genotype, sometimes controlling the size, sex, or behaviour of the offspring. These adaptive maternal effects lead to phenotypes of offspring that increase their fitness. Further, it introduces the concept of phenotypic plasticity, an important evolutionary concept. It has been proposed that maternal effects are important for the evolution of adaptive responses to environmental heterogeneity.
Birth weight is the body weight of a baby at its birth. The average birth weight in babies of European and African descent is 3.5 kilograms (7.7 lb), with the normative range between 2.5 and 4.0 kilograms. On average, babies of Asian descent weigh about 3.25 kilograms (7.2 lb). The prevalence of low birth weight has changed over time. Trends show a slight decrease from 7.9% (1970) to 6.8% (1980), then a slight increase to 8.3% (2006), to the current levels of 8.2% (2016). The prevalence of low birth weights has trended slightly upward from 2012 to the present.
For pregnant women with diabetes, some particular challenges exist for both mother and fetus. If the pregnant woman has diabetes as a pre-existing disorder, it can cause early labor, birth defects, and larger than average infants. Therefore, experts advise diabetics to maintain blood sugar level close to normal range about 3 months before planning for pregnancy.
Neurodevelopmental disorders are a group of conditions that begin to produce symptoms during childhood. According to the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5) published in 2013, these conditions generally appear in early childhood, usually before children start school, and can persist into adulthood. The key characteristic of all these disorders is that they negatively impact a person's functioning in one or more domains of life depending on the disorder and deficits it has caused. All of these disorders and their levels of impairment exist on a spectrum, and affected individuals can experience varying degrees of symptoms and deficits, despite having the same diagnosis.
Protein–energy undernutrition (PEU), once called protein-energy malnutrition (PEM), is a form of malnutrition that is defined as a range of conditions arising from coincident lack of dietary protein and/or energy (calories) in varying proportions. The condition has mild, moderate, and severe degrees.
The thrifty gene hypothesis, or Gianfranco's hypothesis is an attempt by geneticist James V. Neel to explain why certain populations and subpopulations in the modern day are prone to diabetes mellitus type 2. He proposed the hypothesis in 1962 to resolve a fundamental problem: diabetes is clearly a very harmful medical condition, yet it is quite common, and it was already evident to Neel that it likely had a strong genetic basis. The problem is to understand how disease with a likely genetic component and with such negative effects may have been favoured by the process of natural selection. Neel suggested the resolution to this problem is that genes which predispose to diabetes were historically advantageous, but they became detrimental in the modern world. In his words they were "rendered detrimental by 'progress'". Neel's primary interest was in diabetes, but the idea was soon expanded to encompass obesity as well. Thrifty genes are genes which enable individuals to efficiently collect and process food to deposit fat during periods of food abundance in order to provide for periods of food shortage.
The Banting Memorial Lectures are a yearly series of research presentations given by an expert in diabetes. The name of the lecture series refers to Canadian physician Sir Frederick Banting, who was a seminal scientist, doctor and Nobel laureate for the co-discovery of insulin. The lectures are currently hosted by the American Diabetes Association.
Metabolic imprinting refers to the long-term physiological and metabolic effects that an offspring's prenatal and postnatal environments have on them. Perinatal nutrition has been identified as a significant factor in determining an offspring's likelihood of it being predisposed to developing cardiovascular disease, obesity, and type 2 diabetes amongst other conditions.
Maternal obesity refers to obesity of a woman during pregnancy. Parental obesity refers to obesity of either parent during pregnancy.
Prenatal nutrition addresses nutrient recommendations before and during pregnancy. Nutrition and weight management before and during pregnancy has a profound effect on the development of infants. This is a rather critical time for healthy development since infants rely heavily on maternal stores and nutrient for optimal growth and health outcome later in life.
Nutriepigenomics is the study of food nutrients and their effects on human health through epigenetic modifications. There is now considerable evidence that nutritional imbalances during gestation and lactation are linked to non-communicable diseases, such as obesity, cardiovascular disease, diabetes, hypertension, and cancer. If metabolic disturbances occur during critical time windows of development, the resulting epigenetic alterations can lead to permanent changes in tissue and organ structure or function and predispose individuals to disease.
Developmental Origins of Health and Disease is an approach to medical research factors that can lead to the development of human diseases during early life development. These factors include the role of prenatal and perinatal exposure to environmental factors, such as undernutrition, stress, environmental chemical, etc. This approach includes an emphasis on epigenetic causes of adult chronic non-communicable diseases. As well as physical human disease, the psychopathology of the foetus can also be predicted by epigenetic factors.
A predictive adaptive response (PAR) is a developmental trajectory taken by an organism during a period of developmental plasticity in response to perceived environmental cues. This PAR does not confer an immediate advantage to the developing organism; however, if the PAR correctly anticipates the postnatal environment it will be advantageous in later life, if the environment the organism is born into differs from that anticipated by the PAR it will result in a mismatch. PAR mechanisms were first recognized in research done on human fetuses that investigated whether poor nutrition results in the inevitable diagnosis of Type 2 diabetes in later life. PARs are thought to occur through epigenetic mechanisms that alter gene expression, such as DNA methylation and histone modification, and do not involve changes to the DNA sequence of the developing organism. Examples of PARs include greater helmet development in Daphnia cucullata in response to maternal exposure to predator pheromones, rats exposed to glucocorticoid during late gestation led to an intolerance to glucose as adults, and coat thickness determination in vole pups by the photoperiod length experienced by the mother. Two hypotheses to explain PAR are the "thrifty phenotype" hypothesis and the developmental plasticity hypothesis.
The fetal origins hypothesis proposes that the period of gestation has significant impacts on the developmental health and wellbeing outcomes for an individual ranging from infancy to adulthood. The effects of fetal origin are marked by three characteristics: latency, wherein effects may not be apparent until much later in life; persistency, whereby conditions resulting from a fetal effect continue to exist for a given individual; and genetic programming, which describes the 'switching on' of a specific gene due to prenatal environment. Research in the areas of economics, epidemiology, and epigenetics offer support for the hypothesis.
Fetal programming, also known as prenatal programming, is the theory that environmental cues experienced during fetal development play a seminal role in determining health trajectories across the lifespan.
The first 1000 days describes the period from conception to 24 months of age in child development. This is considered a "critical period" in which sufficient nutrition and environmental factors have life-long effects on a child's overall health. While adequate nutrition can be exceptionally beneficial during this critical period, inadequate nutrition may also be detrimental to the child. This is because children establish many of their lifetime epigenetic characteristics in their first 1000 days. Medical and public health interventions early on in child development during the first 1000 days may have higher rates of success compared to those achieved outside of this period.
Kent L. Thornburg is an American scientist, researcher and professor. He lives in Portland, Oregon and works at Oregon Health & Science University (OHSU), in the School of Medicine. He is the director for both the OHSU Center for Developmental Health and the Moore Institute for Nutrition & Wellness
Nutritional epigenetics is a science that studies the effects of nutrition on gene expression and chromatin accessibility. It is a subcategory of nutritional genomics that focuses on the effects of bioactive food components on epigenetic events.