Thrifty phenotype

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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. [1] 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. [2]

Contents

Historical overview

The term thrifty phenotype was first coined by Charles Nicholas Hales and David Barker in a study published in 1992. [3] 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:

  1. The role of beta cell deficiency in type 2 diabetes.
  2. The extent to which beta cell deficiency contributes to insulin intolerance.
  3. The role of major nutritional elements in fetal growth.
  4. The role of abnormal amino acid supply in growth limited neonates.
  5. The role of malnutrition in irreversibly defective beta cell growth.

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. [4]

In a later study, Barker et al. [5] 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. [6] 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 Barker [7] updated 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.

Evolutionary rationale

Offspring

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 [8] [9] ). 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. [10]

Metabolic

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. [8]

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. [11]

Benefit for mother

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 [12]

Other consequences

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. [13] 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. [14] Fetal overnutrition may also play a key role in development, increasing the likelihood of early puberty and obesity. [15]

Adverse effects

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 [16] ). 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 [17] ) 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 [18] ).

Risk factors of thrifty phenotype include advanced maternal age and placental insufficiency. [19]

Molecular mechanisms

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. [20] These changes are also believed to possibly be inherited across generations. [20] Leptin has been identified as a possible gene for the acquisition of these thrifty traits. [20]

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. [19]

See also

Related Research Articles

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<span class="mw-page-title-main">Intrauterine growth restriction</span> Medical condition

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.

<span class="mw-page-title-main">Birth weight</span> Weight of a human baby at birth

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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.

<span class="mw-page-title-main">Protein–energy malnutrition</span> Medical condition

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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.

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Maternal obesity refers to obesity of a woman during pregnancy. Parental obesity refers to obesity of either parent during pregnancy.

<span class="mw-page-title-main">Prenatal nutrition</span>

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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.

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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

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References

  1. ↑ Vaag AA, Grunnet LG, Arora GP, Brøns C (August 2012). "The thrifty phenotype hypothesis revisited". Diabetologia. 55 (8): 2085–2088. doi:10.1007/s00125-012-2589-y. PMC   3390698 . PMID   22643933.
  2. ↑ Hales CN, Barker DJ (2001-11-01). "The thrifty phenotype hypothesis". British Medical Bulletin. 60 (1): 5–20. doi: 10.1093/bmb/60.1.5 . PMID   11809615.
  3. ↑ Hales CN, Barker DJ (July 1992). "Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis". Diabetologia. 35 (7): 595–601. doi: 10.1007/BF00400248 . PMID   1644236. S2CID   35676219.
  4. ↑ Hales CN, Barker DJ (July 1992). "Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis". Diabetologia. 35 (7): 595–601. doi: 10.1007/BF00400248 . PMID   1644236. S2CID   35676219.
  5. ↑ Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM (January 1993). "Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth". Diabetologia. 36 (1): 62–67. doi: 10.1007/BF00399095 . PMID   8436255. S2CID   27195536.
  6. ↑ Phillips DI, Barker DJ, Hales CN, Hirst S, Osmond C (February 1994). "Thinness at birth and insulin resistance in adult life". Diabetologia. 37 (2): 150–154. doi: 10.1007/s001250050086 . PMID   8163048. S2CID   10064670.
  7. ↑ Hales CN, Barker DJ (2001-11-01). "The thrifty phenotype hypothesis". British Medical Bulletin. 60 (1): 5–20. doi: 10.1093/bmb/60.1.5 . PMID   11809615.
  8. 1 2 Hales CN, Barker DJ (November 2001). "The thrifty phenotype hypothesis". British Medical Bulletin. 60 (1): 5–20. doi: 10.1093/bmb/60.1.5 . PMID   11809615.
  9. ↑ Hales CN, Barker DJ (2001). "The thrifty phenotype hypothesis". British Medical Bulletin. 60: 5–20. doi: 10.1093/bmb/60.1.5 . PMID   11809615.
  10. ↑ Barker DJ (September 1997). "Maternal nutrition, fetal nutrition, and disease in later life". Nutrition. Burbank, Los Angeles County, Calif. 13 (9): 807–13. doi:10.1016/s0899-9007(97)00193-7. PMID   9290095.
  11. ↑ Barker DJ (April 1991). "The intrauterine origins of cardiovascular and obstructive lung disease in adult life. The Marc Daniels Lecture 1990". Journal of the Royal College of Physicians of London. 25 (2): 129–133. PMC   5377211 . PMID   2066923.
  12. ↑ Wells JC (February 2007). "The thrifty phenotype as an adaptive maternal effect". Biological Reviews of the Cambridge Philosophical Society. 82 (1): 143–172. doi:10.1111/j.1469-185X.2006.00007.x. PMID   17313527. S2CID   35671934.
  13. ↑ Wells JC (October 2013). "Commentary: The thrifty phenotype and the hierarchical preservation of tissues under stress". International Journal of Epidemiology. 42 (5): 1223–1227. doi: 10.1093/ije/dyt130 . PMID   24159066.
  14. ↑ Payne S, Kumar Bc R, Pomeroy E, Macintosh A, Stock J (June 2018). "Thrifty phenotype versus cold adaptation: trade-offs in upper limb proportions of Himalayan populations of Nepal". Royal Society Open Science. 5 (6): 172174. Bibcode:2018RSOS....572174P. doi:10.1098/rsos.172174. PMC   6030304 . PMID   30110416.
  15. ↑ Robertson OC, Marceau K, Moding KJ, Knopik VS (September 2022). "Developmental pathways linking obesity risk and early puberty: The thrifty phenotype and fetal overnutrition hypotheses". Developmental Review. 66: 101048. doi:10.1016/j.dr.2022.101048. S2CID   252374591.
  16. ↑ Martin P, Bateson P (1999). Design for a life: How behaviour develops. London: Jonathan Cape. pp. 110–1. ISBN   0-224-05064-8.
  17. ↑ Barker DJ, ed. (1992). Fetal and infant origins of adult disease. London: British Medical Journal. ISBN   0-7279-0743-3.
  18. ↑ Robinson R (February 2001). "The fetal origins of adult disease". BMJ. 322 (7283): 375–376. doi:10.1136/bmj.322.7283.375. PMC   1119617 . PMID   11179140. Editorial
  19. 1 2 Aiken CE, Ozanne SE (2013). "Transgenerational developmental programming". Human Reproduction Update. 20 (1): 63–75. doi: 10.1093/humupd/dmt043 . PMID   24082037.
  20. 1 2 3 Stöger R (February 2008). "The thrifty epigenotype: an acquired and heritable predisposition for obesity and diabetes?". BioEssays. 30 (2): 156–166. doi: 10.1002/bies.20700 . PMID   18197594. S2CID   15432962.
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