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Are Children Fighting The “Fat” Gene? An Analysis of Pediatric Obesity and Genetics

/, Genetics, Health and Medicine, Literature Review/Are Children Fighting The “Fat” Gene? An Analysis of Pediatric Obesity and Genetics

Are Children Fighting The “Fat” Gene? An Analysis of Pediatric Obesity and Genetics

2020-08-22T13:29:26-07:00 April 21st, 2019|Biology, Genetics, Health and Medicine, Literature Review|

By Peggy Palsgaard

Author’s Note: I wrote this literature review for my UWP 104F class, and I specifically chose this topic because obesity is a very stigmatized disorder or “disease” (as the AAMC recently labeled it). I wanted to explore the link to genetics and to see how thoroughly we understand the underlying causes of obesity, specifically in children. Further, the judgement of both the children and the children’s parents has brought up a conversation about whether or not it is okay to place a child into foster care for treatment of obesity, due to lack of care by the parents. Initially, research into foster care seemed out of place in this paper. However, I think it’s an interesting way to combine the scientific advancements outlined in this review paper with the social contentions surrounding obesity. I hope the reader will come away with a more thorough understanding of the complexity of the disease based on the link to genetics.

Introduction

Pediatric obesity is a serious disease affecting American children and adolescents.  According to the Center for Disease Control (CDC), one in every six children is affected by pediatric obesity. The CDC defines obesity as having a body mass index (BMI) in the 95th percentile of children with the same age and sex, while morbid pediatric obesity is considered as having a BMI in the 99th percentile.1 Various causes of obesity have been identified, including environmental factors such as diet, level of sedentary lifestyle, and parental BMI. Recently, genetic links to pediatric obesity have been identified and studied. Many genes, including portions of the FTO gene (fat mass and obesity-associated) and 3q29 (a section of DNA on chromosome 3), have been shown to be strongly linked.3,4 Other genes, which were believed to be linked to appetite, have been shown to have no causation with obesity. It is interesting to consider this data in the context of foster care. New studies gathering data from a large sample size of adolescents in foster care have interesting findings. Consideration of this data is important in the discussion of whether or not foster care is an effective treatment option for pediatric obesity. While foster care is not a conventional treatment for obesity, it can be considered in cases where parents are showing neglect.

This review will outline various findings concerning the link between pediatric obesity and genetics. This involves examining studies which suggest a link between genetics and obesity, and also studies which show no causation for a certain gene. Further investigations will be done on publications which outline the changes in BMI after children have entered foster care and the implications of these findings on the causes of pediatric obesity.

Genetic Links

FTO and MC4R

Throughout the past five years, many studies have shown strong genetic links to pediatric obesity. One of these genes is the fat mass and obesity-associated gene, or FTO gene. In one previous publication, researchers utilized a cross-sectional study of over 16,000 children to search for a statistical association between FTO variant rs9939609, total macronutrient intake, and the subsequent effect on BMI.4 They found that this particular FTO variant is predictive of both a high BMI and an associated higher nutrient intake.4  The FTO gene codes for fat mass and obesity-associated protein, which is important in breaking down dietary fats.4 Another research group had a similar question about the FTO gene and variant rs9939609, except they approached the data analysis differently. Rather than looking at whether or not genetic variations modified fat intake, they examined whether or not an increase in macronutrient intake increased the gene’s expression.2 Their findings show that a higher fat intake of an individual increased the activity of the FTO variant.2 The gene expresses itself in a positive feedback manner because the FTO variant rs993609 is predictive of a higher BMI and higher nutrient intake. Further, higher macronutrient intake leads to a higher expression of this variant. This variant has a correlation with and effect on pediatric obesity.4  

Another closely related study looked at the ability of carriers of the FTO GG (a certain genotype of the FTO gene) and/or MC4R CC (melanocortin 4 receptor) gene to lose weight. In order to examine this, researchers screened a large population of obese children and studied those with varying levels of the protein Lp-PLA2, which is the product of FTO GG and/or MC4R CC.3 Obese carriers of these genes were statistically able to lose significantly more weight than non-carriers.3 Certain variants of the FTO gene are associated with weight loss, while others are associated with a higher BMI and a higher fat intake. Both indicate a link between pediatric obesity and genetic factors.

Prader-Willi Syndrome and MO1 Syndrome

Other genetic variants include copy number variants of 3q29 and syndromic, where the patient is showing symptoms (15q11.2 deletions, Prader-Willi syndrome) and non-syndromic (16p11.2 deletion).5.6 A copy number variant is when a portion of the genome is repeated at a different rate than the rest of the population, thus leading to a different number of repeats in the genome of the variant. Prader-Willi syndrome and a deletion of 16p11.2 have been shown to be linked to pediatric obesity, although they are rare deletions.5 Researchers were wondering how significant the relation between rare copy number variants and  pediatric obesity was, so they genetically tested a group of pediatric obese patients versus healthy-weight pediatric patients.5 They found many copy number variants in the obese subject group and concluded that copy number variants statistically contribute to a substantial amount of pediatric obesity cases.5

Other researchers investigated an Arab-Israeli family living in northern Israel. In the family there were 15 obese patients with 31 unaffected, relatively healthy family members. Despite growing up in a very similar environment, with comparable diets and exercise levels, 33% of the family faced obesity with associated glucose intolerance, dyslipidemia (elevated fats and cholesterol in the blood), and insulin resistance.6 While this was not a specific study on pediatric obesity, all affected family members developed childhood obesity by age 3.6 The researchers genetically screened every member of the family and found that all affected by obesity were missing the gene coding for CEP19.6 They verified these results with knockout mice for the same gene. The mice were found to be morbidly obese, glucose intolerant, and insulin resistant, and they also had  a notably increased appetite.6 A wide variety of genetic variations, including mutations, deletions, or insertions, can contribute to the spread of pediatric obesity. Many genes have been investigated and are thought to affect obesity; however, it is important to discuss studies that show no correlations between genetics and obesity.  

Genetics with no causation

While there are many genes which are now thought to be connected to obesity, many have been thoroughly studied and shown to have little relation to obesity. Certain genes which have been linked to appetite were studied to find a link to higher BMI. Genes which code for proteins called Neuropeptide Y and Neuropeptide receptor 2 (NPY and NPY2R, respectively) have been shown to have a positive effect on the appetite of an individual. Since there was a connection to appetite, researchers hypothesized that it may further have an effect on obesity. Adolescents with varying BMIs up to age 14 were screened for overexpression of the previously-mentioned genes and also for genetic variations. This study found no significant variants of NPY2R and some minor variants of NPY, but both these genes were overall found to have no significant contribution to the obese population.7 It is notable to discuss that genes linked to appetite can still be secondarily linked to obesity, even if their expressions can’t be linked to BMI directly. Another study screened for variants of the SH2B1 gene, a gene which codes for a protein which interacts with insulin receptors. The study was broad, and included a large percentage of the Belgian adolescent population. While many variants of the gene were found between healthy and obese subjects, no causation was identified between variants and obesity.8 Researchers do conclude that while causation cannot be statistically verified, it can also not be entirely ruled out.8 In another study on adult Americans, researchers did find a link between SH2B1 and obesity.11 A notable difference between the studies was the age. In Belgium, researchers looked at only adolescents, while the study in America looked only at adults. The juxtaposition of these findings highlight how far we are from a full understanding of this disease and its various causes.

Foster Care

Now that we have examined the link between genetics and obesity, we will examine data connecting foster care and obesity. This is interesting data to analyze for multiple reasons.

Foster care as a treatment for pediatric obesity is currently a heavily-debated, controversial topic. Furthermore, foster care is a dramatic change in a child’s environment. Because of this, we can analyze this data in the context of genetic factors versus environmental factors having an effect on obesity.

There is currently some debate among experts about whether or not foster care is an appropriate option for children who suffer from pediatric obesity, particularly those with morbid obesity. This stems from the idea that parents of obese children do not provide sufficient care by either over-feeding their children or not providing regular, healthy meals. Case studies, where an obese or morbidly obese child is placed into foster care and their weight is studied, are common in this field. A recent study mapped the weight fluctuations of 360 children who were placed into foster care. In children aged 2-5 years, there was a significantly lowered BMI after entering into foster care. However, no significant total change was found across all ages.9 Another similar study compared the BMIs of foster children to standardized normal BMIs in the general population. It was found that children in foster care were more likely to have a higher BMI than children who were not in foster care.10 Foster care has positive and negative effects on each individual child. However, in evaluating a large sample size of children within the foster care system, foster care may not be helpful in treating pediatric obesity and could potentially be contributing to the prevalence of the disease. These findings qualify the previous discussion on pediatric obesity and genetics, as altering a child’s environment does not appear to reduce their BMI and may even lead to an increase in BMI.

Conclusion

While pediatric obesity can have many causes, recent studies have shown a link between genetics and this disease. These findings are particularly interesting in the context of discussing foster care as a treatment option for pediatric obesity. Data suggests that changing a child’s environment by placing them into foster care may have little beneficial effects on pediatric obesity and can even contribute to the disease. Physicians’ current treatment plans for obesity involve recommending lifestyle changes; however, environmental changes will not alter phenotypic effects. With an understanding of the underlying genetic causation, further research could be done on the efficacy of treatment plans for pediatric obesity. Re-evaluation of current treatment plans for pediatric obesity appears important, considering the recent findings about various causes of pediatric obesity.

References

  1. Defining Childhood Obesity (2016). Center for Disease Control. Retrieved from https://www.cdc.gov/obesity/childhood/defining.html
  2. Labayen, I, et. al. (2016) Dietary fat intake modifies the influence of the FTI rs9939609 polymorphism on adiposity in adolescents: The HELENA cross-sectional study. Nutrition, Metabolism and Cardiovascular Disease. 26(10):937-43.
  3. Zlatohlávek, L. (2015) The Impact of Physical Activity and Dietary Measures on the Biochemical And Anthropometric Parameters in Obese Children. Is there any Genetic Predisposition? Central European Journal of Public Health. 3 Suppl:S62-6.
  4. Qi, Q, et. al. (2015) Dietary Intake, FTO Genetic Variants, and Adiposity: a combined analysis of over 16,000 children and adolescents. Diabetes. 64(7):2467-76.
  5. Pettersson, M, et.al. (2017) Copy Number Variants are enriched in individuals with Early-onset Obesity and highlight novel pathogenic pathways.  Journal of Clinical Endocrinology and Metabolism. 102(8):3029-3039.
  6. Shalata, A, et.al. (2013) Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice. American Journal of Human Genetics. 5;93(6):1061-1071.  
  7. Aerts, E, et. al. (2018) Evaluation of a Role for NPY and NPY2R in the Pathogenesis of Obesity by Mutation and Copy Number Variation Analysis in Obese children and Adolescents. Annals of Human Genetics. 82(1):1-10.
  8. Aerts, E, et. al. (2015) Genetic and structural variation in the SH2B1 gene in the Belgian population. Molecular Genetics and Metabolism. 115(4):193-8.
  9. Schneiderman, Janet, et.al. (2013) Weight changes in children in foster care for 1 year. Child Abuse and Neglect. 37(10): 832-840.
  10. Hadfield, S.C., Preece, P.M. (2008) Obesity in looked after children: is foster care protective from the dangers of Obesity? Child: care, health, and development. 34(6):710-2.
  11. Willer, C. J., Speliotes, E. K., Loos, R. J. F., Li, S., Lindgren, C. M., Heid, I. M., … Hirschhorn, J. N. (2009). Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nature Genetics, 41(1), 25–34. http://doi.org/10.1038/ng.287