The Genetics of Obesity: The Thrifty Gene Hypothesis

While this topic has little to do with running, it is pertinent and interesting.  For one of my grad school classes I had to explore the genetic side of Obesity, in particular the Thrifty Gene hypotehsis.  The paper and presentation is below.  My take away from all the research is that the genetic side is incredibly complex and it isn't as simple as there being a few obesity genes or not.  The important thing to remember is that environment and activity levels play a very large role.  Sure we all have different body types and some of us are more likely to put on weight, but the good news is that with proper dietary and exercise practices, you pretty much control your destiny.  First, you'll see the powerpoint and then my paper.



The Thrifty Gene Hypothesis

The recent rise in obesity and type 2 diabetes rates has reached disturbing levels, with over 30% of Americans now classified as obese. This has occurred despite the fact that our knowledge about the importance and effects of diet and exercise are at an all time high. If one were to objectively look at the data on obesity, the only logical conclusion is that we are losing the war on obesity. With many diet and exercise programs failing to produce significant results, the question becomes were we designed for obesity and diabetes?

In 1962 geneticist James Neel proposed the thrifty gene hypothesis to partially explain the rise in Type 2 diabetes in the world (1962). The central premise of this theory is that through natural selection we evolved to be efficient at food storage and utilization. In Neel’s original hypothesis, he stated that ancient humans went through a cycle of feast and famine. The people who had bodies that were better at fuel storage or utilization were more likely to survive during the famine portion of the cycle. Thus over many generations, we developed genetically to be exceptionally efficient at the intake and utilization of fuel as these were beneficial adaptations throughout the majority of human life. However, during the last century the transition to an overabundance of food and limited physical activity limited, has created a situation where our previously advantageous thrifty genes now make us susceptible to diabetes and obesity. In this literature review, the goal will be to look first at the current state of the thrifty gene hypothesis, then at the evidence for and against it and finally to look for new pieces of the puzzle connecting the environment and genetics.

The thrifty gene hypothesis relies on the idea that fuel storage and utilization were important drivers in our history. This is largely viewed through the feat-famine cycle. During periods of famine, adaptations such as larger storage of glycogen or fat might have been advantageous in staving off starvation or hunger related disease. So if a person was more efficient at storing energy during the feasting portion of the cycle, he would be more likely to survive during the famine portion. Similarly, being able to utilize fuel more efficiently, such as a decreased rate of glycogen usage, would similarly stave off death during famine. If left here, the conclusion is often that obesity or an adaptation to easy weight during periods of feasting was an advantage that has subsequently been naturally selected. Critics of the theory point to the fact that weight gain during feast are not substantial (Speakman, 2008). Such critiques are hollow because it only looks at one side of the equation, food storage in the adipose tissue, and ignores another strong influencer, physical activity.

Role of Physical Activity:
What is often left out of the picture is the role physical activity may have had in the development of the thrifty genotype. Chakravarthy and Booth (2004) put forth the theory that the physical activity-rest cycle is just as important as the feast-famine cycle, and that physical activity was integrally linked to food procurement. In the hunter-gatherer society, food was gotten largely through physical activity. Our ancient ancestors have been estimated to have hunt for food for 1-4 nonconsecutive days per week, while women gathered food 2-3 days per week (Chakravarthy and Booth, 2004). Therefore, it makes sense that the humans who were more capable physically of surviving the hunt or gathering food, would survive and pass down their genetics. Thus, physical activity likely played a role. Supporting this idea is the similar physiological responses to feast or famine and to exercise or recovery from exercise. During both feast and recovery from exercise the physiological response is to increase blood glucose, insulin, and muscle glycogen levels while decreasing fatty acid oxidation. Similarly, during famine and exercise, blood glucose, insulin, and glycogen levels decrease, while fatty acid oxidation increases. This shows the intricate linking behind the physiological mechanisms needed during feast or famines and that needed during exercise. It makes sense then that when combined the selective pressure for natural selection is increased. Combining exercise into the thrifty gene hypothesis means that we likely did not evolve just to survive feast or famine, but also to be able to have enough fitness to survive the procurement of food.

This brings us to our current environment which consists of low activity levels, high calorie diets, and positive energy balance. When both the feast-famine and physical activity cycles are removed, as in present day, then the cycling of glucose, insulin, triglyceride, and glycogen usage also stops. Thus, the natural rhythm that is programmed into our genes is stalled, and this results in increased fat storage, diabetes, and other related diseases. Eaton et al. (1988) put it best when they said that we have “ ‘Stone Age’ genes and ‘Space Age’ circumstances.” It is the mismatch between our genetic programming and our environment which has given rise to the obesity epidemic. The complexity of genetics has prevented researchers from finding the magic multiple gene combination which could be considered thrifty, which has made critics of the hypothesis revaluate its role.

What is the driver?
A common criticism of the thrifty gene hypothesis is that severe famines may not have been as frequent as previously assumed (Speakman, 2008). The claim is that a severe famine is needed because death has to be the driver of natural selection, and that while food shortages are common throughout history and have been documented to be occur every decade, severe famines only occur on average of once every 150 years (Speakman, 2008). This would not lead to enough of a differential between death of non-thrifty genetic people and thrifty gene people.

However, we have to consider the impact famine has on birth rates. During famine, individuals have lower body fat levels. It’s been established that low body fat levels impact female reproduction (Prentice et al., 2008). Therefore it’s likely that fertility plays a larger role in the natural selection than previously thought. Humans not adapted to better fuel storage and utilization would be more likely to lose significant fat to the point that reproduction would be impaired. While on the other hand, those better adapted would not lose reproduction ability and would pass on the genotype to the subsequent generation. Further supporting this idea is evidence from studying groups that still go through periods of food shortage. Groups in Gambia and Bangledish for example show a 30-50% reduction in births during their “hungry seasons” during the year (Prentice 2005). As will be discussed shortly, fertility during famines likely plays a role in obesity in other ways too.

Additionally, as mentioned above, I’m not sure of any sources that have taken into consideration the death rates caused by our hunter-gatherer ancestors not being able to endure the physical activity necessary to procure food.

Another source of contention is the timing of such genetic changes. Neel originally proposed that thrifty gene selection started in the early Paleolithic era, while others have suggested that it is a more recent phenomenon and developed during the agricultural era of 10-12,000 years ago (Prentice et al., 2008). Let’s take a look at the potential for each time period.

There is debate over whether hunter-gatherer’s went through periods of severe feast and famine. It’s more accepted that agriculturally reliant humans went through such a cycle (Prentice, 2008). However, this is an unresolved issue and the complexity with which the feast-famine cycle impacts genetic selection makes it difficult to come up with a satisfactory answer. Some evidence for a more recent driver for thrifty genes was found in work done by Voight et al. (2006). They found that genes related to glucose and fat metabolism have been positively selected within the last 10,000 years. This would point to a more recent driving force. But what if we developed the genetic change much earlier?

In looking at the time it would take for natural selection of thrifty genes to occur, Speakman (2008) used accepted calculations to show two potential scenarios. If the force for thrifty genes occurred during the agricultural time period (~12,000 years ago), the genes would not have had time to spread to include much of the population at all. On the other hand, If the force behind thrifty genes occurred during the Paleolithic time, then according to the rate of genetic change, almost all of us should have the thrifty genes. On the surface this seems preposterous because as Speakman says, we should all be obese. However, this is a crucial mistake in reasoning. Just because our genes are designed to be thrifty, does not mean that obesity is the result. Our ancestors, for example, would have had the same thrifty genes if this theory was correct but did not suffer from large amounts of obesity. In fact, modern hunter-gatherer tribes, such as Aborigines, do not show pronounced weight gain (Bribiescas , 2001). The point is that the thrifty gene hypothesis does not say that obesity is advantageous it says that increased fuel storage, utilization, and physical activity efficiency are advantageous. Research shows that the individuals with the most efficient fuel systems are endurance athletes, who by necessity are very thin (Midgeley, 2007). Not coincidentally, well trained runners also have larger glycogen stores, showing that fuel storage and efficiency do not necessarily mean weight gain unless, as in modern society, physical activity and caloric balance are out of whack.

Do we all have Thrifty genes?
Perhaps arguing over the time line of the adaptation is unnecessary. Perhaps we’ve been designed with thrifty genes the whole time? This is the hypothesis that Roger Stoger (2008) put forth in stating that we all have thrifty genotypes, not just obese individuals. His contention is that because energy efficiency and fitness was essential to early man, “unthrifty” genes never were allowed to become established. Thus, we all have thrifty genes. This makes sense when combined with the recent theory that suggests humans evolved to become endurance runners (Bramble & Lieberman, 2004). Perhaps obesity or weight gain was never a driving force during the feast-famine cycle, but instead we have evolved to become efficient at fuel storage, utilization, and exercise because it has been necessary sense the development of our species. Problems arise when there is a mismatch between what we were designed to do, and what we currently do, thus obesity, diabetes and similar diseases develop. Along those lines, a newer field of study provides some missing clues into the theory of thrifty genes.

The Epigenetics of Obesity
If we all have thrifty genes, then why is obesity seemingly more heritable in certain groups like the Pima Indians then others? The answer according to some comes from having a thrifty epigenome. While we are all concerned with if we have or don’t have a specific genetic allele, recent evidence suggests that perhaps how that gene functions is more important. The field of epigenetics has shown that the body can manipulate the degree of transcription, or activation, a particularly gene has. Even more astounding is that environmental factors can impact the epigenome within a lifetime, thus altering how a gene functions. It’s best thought of as genes being the hardware, while epigenetics are the software that allow subtle manipulation. This epigenome is the way for the human body to make short term adaptations to the environment and that change in the epigenome can be passed on to subsequent generations through a process called genetic imprinting. Genetic imprinting in obesity related genes already have been found (Dong et al. 2005), demonstrating the passing on of obesity related epigenetic changes.

While the field is new, research shows that epigenetic changes largely occur when the baby is in development. The mother’s nutrition for example can cause epigenetic changes for the baby. It’s thought that this occurs to match the unborn baby to it’s outside environment. Thus, if the baby is in development during a famine, the genes related to food storage will be up regulated to prepare it for the famine environment it’s about to enter. Problems occur, when the outside environment no longer matches the environment the baby was prepared to enter. This so called mismatch concept states that disease, such as diabetes or obesity, likely occurs when the mismatch between expected environment when epigenetic changes are high does not match the outside environment later in life (Godfrey et al., 2007).

Evidence for this mismatch concept can be seen in the Ravelli et al. (1976) study which looked at the consequences of a famine in the Netherlands in 1944-45. They found that obesity was much higher in those whose mothers went through famine during their first two trimesters of pregnancy. Essentially, according to Stoger and his “thrifty epigenome” hypothesis, we are preprogrammed with a certain metabolic profile, and when our food intake and physical activity does not match this profile, obesity and diabetes is likely to occur.
This would explain why the Pima Indians, for example, seem to overreact and become obese at a much higher rate than others. They went from an expected environment filled with physical activity and a traditional diet, like that seen in the Mexican side of the group, to a high calorie American diet with little activity. The rapid rise in obesity in a matter of two generations would also partially be explained by this new evidence. A critic might point out that after one generation, then we should see obesity rates drop because the epigenome of new babies would adapt. However, this does not take into account the negative environmental factors that still play a large role. Even if the body is designed to be “thin” if enough calories and a sedentary lifestyle is undertaken, obesity can still occur. Secondly, genetic imprinting on the epigenome is passed on to multiple generations, so it is possible that it could be several generations before the epigenome adapts to the environment. Further research needs to be done to elucidate these ideas.

As can be seen, the genetics of obesity and the thrifty gene hypothesis are a complicated subject. It is easy to accept or dismiss portions of the hypothesis based on select data, but when taken in full it is clear that we simply do not understand everything that goes into the relationship between genetics and obesity. The genetics of obesity are not like other diseases where a single gene variant is the major player. Instead, obesity is a polygenic problem, meaning that the interaction between numerous genes may contribute to the issue. Further muddling the picture is the fact that it not only matter whether one has a combination of genes, but how they function. For this reason, it’s no surprise that the magic combination of genes that make one obese hasn’t been found. Only recently has the role of the epigenome been discovered and future possible findings could impact our interpretation of the thrifty gene hypothesis. While we could argue over the drivers of the hypothesis, it is more productive to look at such ideas as the mismatch concept and see if it is indeed a mismatch between expected and actual environment which is causing us so many problems.


References
Bramble, D. M. & Lieberman, D. E. (2004). Endurance running and the evolution of Homo. Nature, 432, 345–352.
Bribeescas, R. G. (2001). Serum leptin levels and anthropmetric correlates in ache Amerindians of eastern Paraguay. Am J Phys Anthropol, 115, 297–303.
Chakravarthy, M. V. & Booth, F. W. (2004). Eating, exercise, and “thrifty” genotypes: connecting the dots toward and evolutionary understanding of modern chronic diseases. J Appl Physiol, 96(1), 3–10.
Dong, C., Lie, W. D., Geller, F., Lei, L., Li, D., Gorlova, O. Y., Hebebrand, J., Amos, C. I., Nichols, R. D. & Price, R. A. (2005). Possible Genomic Imprinting of Three Human Obesity–Related Genetic Loci. The American Journal of Human Genetics, 76(3), 427–437.
Eaton, S. B., Konner, M. & Shostak, M. (1988). Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Am J Med, 84, 739–749.
Godfrey, K. M., Lillycrop, K. A., Burdge, G. C., Gluckman, P. D. & Hanson, M. A. (2007). Epigenetic mechanism and the mismatch concept of the developmental origins of health and disease. Pediatric Research, 61(5), 5–10.
Midgeley, A. W., McNaughton, L. R., & Jones, A. M. (2007). Training to enhance the physiological determinants of long-distance running performance: can valid recommendations be given to runners and coaches based on current scientific knowledge. Sports Med, 37(10), 857–880.
Neel, J. V. (1962). Diabetes mellitus a ‘thrifty’ genotype rendered detrimental by ‘progress’? Am J Hum Genet, 14, 352–353.
Prentice, A. M., Hennig, B. J. & Fulford, A. J. (2008). Evolutionary origins of the obesity epidemic: natural selection of thrifty genes or genetic drift following predation release? Internationa Journal of Obesity, 32, 1607–1610.
Prentice, A. M. (2005). Starvation in humans: evolutionary background and contemporary implications. Mech Ageing Dec, 126, 976–981.
Ravelli, G. P., Stein, Z. A. & Susser, M. W. (1976). Obesity in young men after famine exposure in utero and early infancy. N Eng J Med, 295, 349–353.
Speakman, J. R. (2008). Thrifty genes for obesity, an attractive but flawed idea, and an alternative perspective: the ‘drifty gene’ hypothesis. International Journal of Obesity, 32, 1611–1617.
Stoger, R. (2008). The thrifty epigenotype: an acquired and heritable predisposition for obesity and diabetes? BioEssays, 30(2), 156–166.
Voight, B. F., Kudaravalli, S., Wen, X. & Pritchard, J. K. (2006). A map of recent positive selection in the human genome. PLoS Biol, 72.

11 comments:

  1. Excellent post. In this day and age I feel everyone either wants an "excuse" or a "magic bullet."

    But you pretty much summed it up, "Sure we all have different body types and some of us are more likely to put on weight, but the good news is that with proper dietary and exercise practices, you pretty much control your destiny."

    ReplyDelete
  2. Anonymous8:16 AM

    Haven't read your pos in detail yet, but it's fascinating. Just to add something I'm reading at the moment.

    http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.686.html

    The largest study up till now on genes and obesity. Researchers estimate that 8 to 10 kg extra can be contributed to genes.

    ~ Chi

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  3. Great post. Thanks for pointing out the complexity. The sheer amount of genes involved makes it unlikely, that everyone is endowed with thrifty genes. Even a simple complication like dominance of some 'obese' gene over a 'slender' gene would ensure the survival of a slender genotype, save a consistent 100% mortality before reproduction of the slender genotype over many genrations.

    If you need some more recent references on the effects of the 1944-1945 famine:

    http://ihome.ust.hk/~lbcaplan/dutchfamine.html

    ReplyDelete
  4. Anonymous11:00 AM

    great post-thanks

    ReplyDelete
  5. Very good, detailed analysis of the current research. I think a lot of non-science folk get hung up on the "one gene, one disease" and are looking for a magic bullet to "cure" obesity, so it's good to see people like you laying it all out and saying "hey! It's much more complicated!".

    I've seen people I know (in particular, my brother and sister-in-law) use exercise and careful control of diet to obtain some great results, regardless of whether the genes indicate they should or not (my brother went from ~255 to ~210 over the last two months!). While we can try to blame genes, it's really how we work with what we have that makes the difference!

    Again, great post!

    ReplyDelete
  6. I like the inclusion of Bramble and Lieberman's evolution position. I just heard Lieberman speak last weekend in NY and he makes a very convincing argument. Dovetailing into Lieberman is Robb Wolff's Paleo Solution (and Paleo Diet) that identify grain (whole or not), legumes and dairy as the culprits behind everything from diabetes to cancer to depression. If the single most significant change in modern man was the shift from hunter gatherer to agrarian society then its only in the past 3,000 or so years that man has set himself up to be unhealthy.

    The concept is that over hundreds of thousands of years, we were wired to eat lean meats, veggies, nuts and seeds. In only the last 3,000 years have we begun eating "new" foods, foods our bodies are not designed or adapted to process. While these foods do support massive population growth, they also wreak havoc on our gi tract, liver, gall bladder, etc. To me it only makes sense, if these new foods are the foundation of the American diet, that primetime TV hours are filled with pharmaceutical solutions to all the health issues stemming from our consumption of grains, beans and dairy.

    Here's my disclaimer. I haven't finished reading the book yet and I am only in the beginning stages of practicing a paleo diet myself. Nonetheless, I think the info from Webb is worth sharing here.

    Always interesting stuff here Steve. Thanks.

    ReplyDelete
  7. Thanks for the comments everyone.

    Andrew- I think we have to be careful with the Paleo stuff. In particular I don't like the fact that they attribute one particular thing as the cause of all sorts of varying diseases.

    Grains aren't evil, fat isn't evil, sugar isn't evil.

    We get in trouble when we take in too much and do too little.

    Anyways, I think that the Paleo diet stuff sometimes simplifies things too much and makes vast conclusions on simplified models. It's not as simple as saying our genes aren't adapted to certain kinds of foods. It depends on too many factors. For instance, certain populations have developed the enzyme to digest milk, others largely lack it.

    Anyways, the point is that making stuff out to be "evil" doesn't work. Look at the Fat is evil craze that started in the 70's and the Carbohydrate is evil phase that started in the 90's.

    It's a complex problem. We have groups who are perfectly healthy eating high amounts of sugar, fat, or protein. The key is the balance.

    ReplyDelete
  8. Thanks for responding Steve.

    The book is actually pro-fat, not anti. Grains and sugar are attacked pretty hardily though. The diet, seems to closely resemble Atkins (which I've never practiced). I am actually doing the simplifying via my short posts.

    Bottom line is, I agree with you that diet is very complex and should not be oversimplified. The book does offer a good deal of science behind its premise (stuff you would understand better than me). I am not the fanatical type. I come to your site because I seek knowledge and I seek challenges to health and fitness dogma. Basically I look for a balance in all the information available. As you say, "the key is balance."

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  9. Very informative post. Loving this comparison...

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  10. Anonymous12:44 AM

    I totally agree that it's much more complex than someone tries to show. Now there is very popular thing to adjust ratio of carbs/protein/fats for each individual through metabolic typing. Could be some truth behind it? There are many examples how one person could strive on particular diet while another feel sick. Whatever it would be vegetarian, Atkins, Paleo and ect. Some vegans feels great, some not so. Some are more insulin resistant others insulin sensitive. People who are insulin resistant feel great with higher percentage of protein and fat, while insulin sensitive can feel great with higher amount of carbs. For sure there are people who are fexible to various ratios and foods. Many people who are obese simply simply consume too many calories. Why they consume too much and don't use them it's another question.

    ReplyDelete
  11. I may have to say that this is a helpful and insightful post. I remember my long island dietician who keeps on telling me that it is helpful to read blogs that tackle obesity, and I may have to say that It works for me and now I’m happy with the results.

    ReplyDelete

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