Study: obesity congenital

Geschatte leestijd: 5 minuten

40 to 75 percent of overweight could be explained by genetic differences. What are these obesity-causing genes and how do you identify them?

Overweight: More Than a Single Cause

When treating overweight, there is a tendency to quickly search for a single, all-explaining cause. Not only when treating overweight, by the way. Simplifying things more than they are is a popular method of conveying certain information. After all, no one likes complex problems.

But some problems are simply complex. Overweight can be caused by various factors. Of course, it all ultimately comes down to how much energy comes in versus how much energy you expend. But those two variables can be influenced by many possible factors, from socioeconomic background to pollution, infections, and stress [1,2].

Diet books can sell well by pointing to a single culprit like sugars and fats. Or by suggesting a single solution like the amount of water to drink or a certain detox regimen. The reality is not so simple.

Genes and Overweight

One of the most difficult questions to answer is to what extent behavior can influence your weight and to what extent this is determined by innate factors. It is known, however, that genes can play an important role in determining your weight [3].

According to some studies among twins, overweight can be explained by 40 to 75 percent due to innate characteristics [4]. This influence turned out to be much greater than the influence of the environment.

These kinds of genetic variations among people are called single-nucleotide polymorphisms (SNPs). Genes enable the production of certain proteins. Variations on the gene can lead to changes in the protein that can be made with it. These proteins then influence various types of tissues in various ways.

Fat mass and obesity-associated

There are some known genetic mutations that offer a higher chance of overweight [5]. One of the genes that can show such a variation is even named after its effect on fat mass; Fat mass and obesity-associated (FTO). Other examples of such genes are Perilipin (PLIN) and β-adrenergic receptor 3 (ADRB3). When British researchers examined the effect of nearly half a million SNPs in almost 5,000 Britons, the role of FTO stood out. Certain variations on this gene were associated with higher weight and a greater risk of type 2 diabetes [8].

FTO plays a role in the amount of food you eat and drink [6]. The gene encodes an enzyme that works in the hypothalamus. Variations on this gene have been linked to appetite regulation and higher food intake [7,8].

Perilipin 1

Perilipin 1 is a protein present in fat cells. It plays an important role in the storage and utilization of fat by covering the fat droplet and protecting it from the actions of enzymes [9]. These enzymes are responsible, among other things, for the burning of these fatty acids. The PLIN gene codes for this protein, and various variations on PLIN are known to play a role in the development of obesity or protect against it [10,11].

In a study of nearly 1600 Spanish women, the variations PLIN1 and PLIN4 were found to have a significant association with a lower BMI. In that case, the gene does not do its job as well, so the perilipin 1 protein can block the fat-burning action of these enzymes to a lesser extent.

β-adrenergic receptor 3 (ADRB3)

The reverse applies to beta 3-adrenergic receptor (ADRB3).

The beta 3-adrenergic receptor is mainly found in adipose tissue. This receptor is involved in regulating fat burning and increasing body temperature. The role is to reduce fat mass.

In a French study, the effect of a certain variation on this gene, Trp64Arg, was examined. This variation changes the protein it codes for by replacing the amino acid tryptophan at position 64 with arginine [12].

This variation was found to result in an (even) higher weight in the group of people with severe obesity. Apparently, the receptor is less able to perform its fat-burning function due to this variation. The average weight in the group without this variation was 127 kg. In the group with this variation, it was 140 kg.

The Search Continues

These are just a few examples.

There are thousands of genes, each with several possible variations. Ultimately, the effects of all those variations, independently and in combination with other variations, must become clear.

For the future, this could mean that on a personal basis, you can increasingly gain insight into your risk profile for overweight. You can then know whether your large appetite or low metabolism is (partly) caused by genetic variations.

Is that useful? Yes, because it can prepare you for the fact that you may need to make more effort to lose weight than others. This can prevent disappointment and giving up.

On the other hand, gene doping could offer a solution in the future. By means of a virus, certain genes can be permanently modified. If you can get rid of annoying genetic variations in this way or even cause positive variations, a normal weight becomes possible and easier for everyone.

References

1. McAllister EJ, Dhurandhar NV, Keith SW, Aronne LJ, Barger J, Baskin M, et al. Ten putative contributors to the obesity epidemic. Crit Rev Food Sci Nutr. 2009;49:868–913. doi: 10.1080/10408390903372599.
2. Madrigano J, Baccarelli A, Wright RO, Suh H, Sparrow D, Vokonas PS, et al. Air pollution, obesity, genes and cellular adhesion molecules. Occup Environ Med. 2010;67:312–317. doi: 10.1136/oem.2009.046193.
3. Cummings DE, Schwartz MW. Genetics and pathophysiology of human obesity. Annu Rev Med. 2003;54:453–471. doi: 10.1146/annurev.med.54.101601.152403.
4. Wardle J, Carnell S, Haworth CM, Plomin R. Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. Am J Clin Nutr. 2008;87:398–404.
5. Kaur Y, de Souza RJ, Gibson WT, Meyre D. A systematic review of genetic syndromes with obesity. Obes Rev. 2017;18:603–634. doi: 10.1111/obr.12531.
6. Gerken T, Girard CA, Tung Y-CL, Webby CJ, Saudek V, Hewitson KS, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318:1469–1472. doi: 10.1126/science.1151710
7. Qi Q, Kilpelainen TO, Downer MK, Tanaka T, Smith CE, Sluijs I, et al. FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals. Hum Mol Genet. 2014;23:6961–6972. doi: 10.1093/hmg/ddu411.
8. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science NIH Public Access. 2007;316:889–894.
9. Brasaemle DL, Rubin B, Harten IA, Gruia-Gray J, Kimmel AR, Londos C. Perilipin a increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. J Biol Chem. 2000;275:38486–38493. doi: 10.1074/jbc.M007322200.
10. Qi L, Corella D, Sorlí JV, Portolés O, Shen H, Coltell O, et al. Genetic variation at the perilipin (PLIN) locus is associated with obesity-related phenotypes in white women. Clin Genet. 2004;66:299–310. doi: 10.1111/j.1399-0004.2004.00309.x.
11. https://www.ncbi.nlm.nih.gov/pubmed/15355432
12. Mottagui-Tabar S, Rydén M, Löfgren P, Faulds G, Hoffstedt J, Brookes AJ, et al. Evidence for an important role of perilipin in the regulation of human adipocyte lipolysis. Diabetologia. 2003;46:789–797. doi: 10.1007/s00125-003-1112-x.
13. Clément K, Vaisse C, Manning BS, Basdevant A, Guy-Grand B, Ruiz J, et al. Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med. 1995;333:352–354. doi: 10.1056/NEJM199508103330605.
14. PPAR gamma and the control of adipogenesis. Spiegelman BM, Hu E, Kim JB, Brun R Biochimie. 1997 Feb-Mar; 79(2-3):111-2.