Arya M. Sharma, MD

Yesterday, I posted about the observations that the same genes that confer athletic ability by increasing ‘fuel efficiency’ may also promote obesity when such activity ceases. This is in line with the ‘thrifty gene’ hypothesis, that obesity is the ‘natural’ response to genes that conferred survival advantages in our ancestors in the face of famines and increased demands on physical activity.

Interestingly, a study by Abdoulaye Diane and colleagues from the University of Alberta, just published in OBESITY, demonstrates that genetically obesity-prone animals, do in fact have a considerable survival advantage over lean-prone animals, an advantage that is further enhanced, when such animals have previously experienced caloric restriction.

The researchers took advantage of the fact that limiting access to food in mice (by restricting feeding hours) leads to an incremental increase in ‘voluntary’ wheel running associated with reduced food consumption (activity-induced anorexia) and even more running till the animals ultimately exhaust themselves and die.

In their experiments, while food restriction resulted in increased wheel running and reduced food intake in both obesity-prone and lean-prone juvenile mice, the former survived almost twice as long and lost far less of their body weight (percent and absolute values) than the lean-prone mice, which rapidly succumbed to the challenge.

Furthermore, even obesity-prone rats, who were kept lean by restricting their food to the levels of the lean-prone rats (by ‘pair-feeding’), lived longer, suggesting that this was not an advantage conferred simply by greater ‘caloric reserves’.

Interestingly, obesity-prone juvenile mice, who had previously undergone food restriction and regained their weight prior to the challenge, did even better.

Thus, not only was there a clear survival advantage in the genetically obese-prone mice but previous food restriction appeared to confer even more ‘resistance’ to the challenge.

It appear that not only do ‘obesity-prone’ genes allow animals to better cope with the dual challenge of starvation and increased physical activity, but that this ‘metabolic’ prowess can be further enhanced by prior experience with food restriction (weight loss).

Translated to humans, this later finding would suggest that ‘dieting’ makes you even more fuel efficient (which may well explain why dieting increases the risk of subsequent weight gain).

Or as the authors discuss:

“Our results show that juvenile obese-prone rats gain a survival advantage over lean-prone under famine-like conditions, and this advantage is further enhanced by physiological and behavioral changes induced by prior food restriction. In the wild, this survival advantage in young animals, that are the future breeders, would confer increased reproductive success. At a basic level, these results support the “thrifty gene” hypothesis of obesity.”

The authors further conclude:

“Thus, caloric restriction at early ages may predispose obese-prone individuals to become more metabolically efficient. An inducible increase in metabolic efficiency may help to explain the increased obesity in low- and middle-income countries where childhood under-nutrition exists in the context of rapid economic development and rural/urban migration. Thus, the obese-prone phenotype, that is highly deleterious in a food-rich environment, confers a real survival benefit in an unstable and scarce food environment, that is enhanced by prior caloric restriction.”

In summary, if these findings are indeed transferable to humans, they would have several important implications:

1) Genetically obese-prone individuals are better equipped to survive times of scarcity and/or increase physical demand.

2) This ’survival’ advantage can be further enhanced by previous exposure to caloric restriction (weight loss).

While these findings may also explain the ’survival paradox’ of obesity, where obese humans with chronic illnesses tend to live longer than skinny people with those illnesses, they also suggest an explanation for why dieting can make you fat.

I certainly do not envy the folks, who have to translate these findings into coherent ‘public health’ recommendations:

a) having genes that promote obesity is actually a survival benefit (if you should happen to encounter a famine)

b) if you are lucky enough to have these obesity genes, you can further increase your survival benefit (to famines) by (periodically?) losing weight

c) however, if you do (periodically?) lose weight, you may also end up getting even more obese - which, although a survival benefit during the next famine, will increase your risk for obesity-related health problems (in case the famine does not come).

I guess you can’t have it all.

AMS
Calgary, Alberta

Diane A, Pierce WD, Heth CD, Russell JC, Richard D, & Proctor SD (2011). Feeding History and Obese-Prone Genotype Increase Survival of Rats Exposed to a Challenge of Food Restriction and Wheel Running. Obesity (Silver Spring, Md.) PMID: 22016097

One of the interesting but ‘paradoxical’ observations in my clinical practice is the rather large number of patients presenting with severe obesity, who have histories of successful competitive sports careers.

I have previously written about the notion that perhaps the same genes that can make you a successful athlete may well pose a risk factor for obesity.

Now, a study by Xue and colleagues from the University of Texas, published in PLoS One, suggests that genes that increase metabolic efficiency may indeed explain both the higher athletic prowess as well as the increased risk for obesity in Africans.

It is certainly no secret that Africans have held the most world records for track and field sports, including the men’s and women’s 100-meter dash, 200-meter dash, 400-meter dash, 800-meter dash, and even marathons.

Based on previous observations that Africans tend to expend less energy for the same level of physical activity as Europeans, the researchers reasoned that the genes responsible for this may also contribute to an increased predisposition to weight gain in this population.

The researchers used data from the HapMap project to examine African, Asian and European subjects for 231 common variants with possibly harmful impact on 182 genes involved in energy metabolism

This analysis found that Africans (3 out of 4 groups) had a significantly smaller genetic risk in the of possessing genes that would lead to inefficient energy metabolism than Europeans and Asians

As they point out:

‘In sport competitions, athletes need massive amounts of energy expenditure in a short period of time, so higher efficiency of energy generation might help make African-descendent athletes more powerful. On the other hand, higher efficiency of generating energy might also result in consuming smaller volumes of body mass. As a result, Africans might be more vulnerable to obesity compared to the other races when under the same or similar conditions.”

Obviously, as there is no such thing as the ‘African’ genome, in that all such genetic variants are also found in non-Africans, it may be reasonable to speculate that in general, genes that improve energy-efficiency (or rather absence of genetic variants that reduce it), thus increasing athletic prowess, can contribute to increased risk for obesity (when exercise ceases) in all populations.

While this notion is not dissimilar to the ‘thrifty genotype’ hypothesis, it does provide a novel ’spin’ in that it suggest that the same ‘thrifty genotype’ that promotes obesity may also be responsible for making you a good athlete.

This certainly sounds very plausible considering how many obese patients I see, who have histories of being successful athletes. It also perhaps explains why so many of my patients can maintain rather high levels of physical activity once they find their way back into sports (for e.g. after bariatric surgery).

AMS
Edmonton, Alberta

Xue C, Fu YX, Zhao Y, Gong Y, & Liu X (2011). Smaller genetic risk in catabolic process explains lower energy expenditure, more athletic capability and higher prevalence of obesity in africans. PloS one, 6 (10) PMID: 22016803

The melanocortin system is one of the key systems involved in the regulation of ingestive behaviour. Thus, for example, genetic variants of the melanocortin type 4 receptor (Mc4R), have been found to be among the most common mutations associated with severe obesity (in about 5% of cases).

Other studies have also suggested a role for the Mc3R in the regulation of weight gain and food intake, especially with regard to its relationship to circadian rhythms. This is perhaps not surprising, given that the ventromedial hypothalamus (VMH), a critical node in the neural networks regulating feeding-related behaviors and metabolic homeostasis, exhibits dense Mc3R expression relative to other brain regions. In addition, Mc3R is also expressed in the limbic system as well as in peripheral tissues.

A study by Karima Bergriche and colleagues from the Scripps Research Institute, just published in the Journal of Biological Chemistry, shows that the Mc3R may affect body fat and food intake through both central and peripheral mechanisms.

Using a combination of Mc3R knockout mice with neural specific Mc3R expression, the investigators were able to dissect the role of these receptors and brain regions in food intake and metabolism.

Thus, although the knockout animals displayed reduced lean mass, increased fat mass, and accelerated diet-induced obesity (DIO), the attempt to rescue these mice by Mc3R expression in their nervous systems only partially rescued obesity in chow-fed conditions, and had no impact on the accelerated DIO phenotype.

More specifically targeting Mc3R expression to the VMH, despite marked improvements in metabolism also had little impact on obesity.

The authors interpret this findings to indicate that MC3Rs affect energy homeostasis through both central (neuronal) and peripheral mechanisms and that the effects of these receptors on behavior and metabolism involve divergent pathways.

Or, as the authors put it:

“Our data suggests that actions of MC3R in these neurones significantly impacts on metabolic homeostasis, but is not sufficient restore body composition to normal or for regulating expression of complex behaviours associated with food anticipation.”

Clearly, better understanding the pathways and mechanisms involved in these effects may lead to drugs that can perhaps help target this system to improve metabolism and treat obesity.

As always, what works in animals, does not necessarily directly lead to effective and safe medications for humans. Nevertheless, identifying drugable targets is certainly the first first step towards hopefully finding better treatments for obesity and related metabolic problems.

AMS
Edmonton, Alberta

Begriche K, Levasseur PR, Zhang J, Rossi J, Skorupa D, Solt LA, Young B, Burris TP, Marks DL, Mynatt RL, & Butler AA (2011). Genetic dissection of melanocortin-3 receptor function suggests roles for central and peripheral receptors in energy homeostasis. The Journal of biological chemistry PMID: 21984834

Imagine that there were people with a genetic predisposition to asthma. Many different genes are involved - the more ‘asthma’ genes you have - the more severe your asthma.

Now imagine that people with a high genetic risk, a moderate genetic risk, a substantial genetic risk and a severe genetic risk for asthma were all living out in cottage country, where there is clean air with no air-borne dust or pollutants. Only those few individuals unfortunate enough to have ’severe’ genetic risk would have asthma - everyone else would be perfectly fine.

Researchers studying the relationship between asthma and genetics in cottage country would find that in most people genes have no effect on asthma symptoms and only in people with very severe asthma would there appear to be some genetic influence.

Now imagine that a busy highway is built straight through that community with lots of heavy car and truck traffic that significantly reduces air quality.

Now, even those with low genetic risk will start wheezing, those with moderate risk will start coughing, those with substantial risk will no longer be able to do heavy work outside, and those with the most severe risk will be confined to their beds under an oxygen tent.

Suddenly, researchers studying this community, will find that there is a close relationship between genetic risk and asthma symptoms - indeed, the difference between those who have no, some, moderate, substantial or severe asthma can almost entirely be explained by genetics. In fact, in those with any symptom of asthma - the entire ‘variance’ will be found to be almost completely attributable to their genetic risk - suddenly genes become the most important determinant of who has symptoms and who doesn’t!

Not surprisingly, exactly the same is true with obesity, according to a large twin study by Benjamin Rokholm and colleagues from the University of Copenhagen, published in the latest edition of PLoS One.

The researchers examined data on 15,017 monozygotic and dizygotic twin pairs born between 1931 through 1982.

Using classical twin-study methodologies, they found that the additive genetic variation was positively and significantly associated with obesity prevalence and the mean of the BMI distribution.

In other words, as the prevalence of obesity, prevalence of overweight and the BMI mean increased, so did the ‘genetic’ variation in BMI.

As in the theoretical asthma example, these findings are consistent with the notion that variations in genes related to body fatness are more important and lead to greater weight gain under the influence of an obesity-promoting environment.

While this study points to the idea that we need to get serious about tackling the environmental drivers of obesity, it also means that in the meantime, the existing environmental factors will disproportionately affect those with the greatest genetic risk.

So, while everyone is sedentary, get too little sleep, is stressed out and, therefore, eats too many calories - those with the greatest genetic load will gain the most weight, while those with no genetic risk will be just fine (we all know these people).

From a health services perspective this means that, while we wait for policy makers to pass new laws that will help reverse the many obesogenic factors in our current environment (which is likely to take as long as it will take them to reverse global warming), we need to provide appropriate help and care to those who are suffering the consequences from having chosen the wrong parents.

Genetics does not mean you cannot do anything about it - it just means that those with a greater genetic risk need to do much more (often with professional help) to manage their weight than those who happen to have lower genetic risk.

Of course it is also not helpful to tell those with the highest genetic risk to simply live like those with no genetic risk - because that is already exactly what they are doing - unfortunately, they have to do far more!

Sure, the best way to get our severe asthma patient out of the oxygen tent would be to shut down the highway (or mandate cleaner cars) - in the meantime, however, let’s make sure there’s enough oxygen flowing into the tent for those who need it.

AMS
Edmonton, Alberta

Rokholm B, Silventoinen K, Angquist L, Skytthe A, Kyvik KO, & Sørensen TI (2011). Increased Genetic Variance of BMI with a Higher Prevalence of Obesity. PloS one, 6 (6) PMID: 21738588

Regular readers of these pages may be well aware that there are considerable variations in how individuals respond to changes in their diets and activity levels. Some people lose weight on some diets, others don’t - some people eat less food when they exercise, others eat more.

The same applies to almost any variable that has been measured - people simply respond differently to different interventions - diet, lifestyle, medications, or even surgery.

One of the key determinants of how individuals respond, is certainly genetic. Thus, for example, a considerable body of evidence supports the notion that the response of cardiovascular risk factors like blood pressure, lipids, insulin resistance, etc. to exercise are highly heritable - in other words, some people experience significant improvements - others, performing the same amount of exercise, don’t.

So far, however, exactly which genes (let alone which variants of these genes) could determine this variability in response is largely unclear.

Nevertheless, researchers working in genetics (and the many companies involved in developing genetic tests), justify their considerable efforts with the promise of ‘personalised’ medicine, which would allow to predict disease risk and thereby allow people to adopt behaviours that could mitigate such risk (although so far there is virtually no evidence that telling people that they are at higher genetic risk for anything has any impact on their behaviours - in fact, some folks may rather take a fatalistic approach and simply decide to continue eating, drinking, and being merry).

The reason why we should probably not be holding our breath in anticipation of a genetic test that will predict who will benefit most (or least) from exercise is now outlined in an article by Jim Hagberg from the University of Maryland, published in the latest issue of the Journal of Applied Physiology.

Thus, although there is some evidence supporting “possible” candidate genes that may affect responses to exercise training - APO E and CETP for plasma lipoprotein-lipid profiles, eNOS, ACE, EDN1, and GNB3 for blood pressure, PPARG for type 2 diabetes phenotypes, and FTO and BAR genes for obesity-related phenotypes - there is one very significant barrier to advances in this field.

This limitation relates to the fact, that one would need to generate vast amounts of data from exercise interventions studies - an undertaking that may be both unfundable and unfeasible.

The need for such large sample sizes is becoming more and more evident, as attempts to find genes for diabetes, obesity or blood pressure, despite utilizing populations of 10,000 to 250,000 subjects, have found few genes that have largely minor effects - too small to have any clinical utility in predicting these conditions with any reasonable sensitivity or specificity.

As the impact of individual genes on exercise responses are likely to be of similar magnitudes, one would need to perform exercise studies in 10s of thousands of individuals to have any hope of ever finding the genetic determinants of exercise response.

This does not mean that genetics is not an important determinant of exercise response - it just means that finding the genes responsible for differences in responses is a virtually hopeless undertaking.

The same is likely true for other attempts at finding genes to predict individual responses to ‘lifestyle’ interventions.

It may well be that ‘personalised’ medicine in the future will largely be no different from ‘personalised’ medicine today, consisting namely of listening to your patients relating their personal concerns or problems and using your best judgement, your interpretation of clinical evidence (where available) and your (hopefully extensive) clinical experience to advise them the best you can.

When you think about it, it seems quite funny how the use of the term ‘personalised’ medicine in the context of genetic testing, if it ever becomes a reality, will actually result in a further ‘depersonalisation’ of medicine - sounds a lot like Orwelian Douplespeak to me.

AMS
Edmonton, Alberta

Hagberg JM (2011). Do Genetic Variations Alter the Effects of Exercise Training on Cardiovascular Disease and Can We Identify the Candidate Variants Now or In the Future? Journal of applied physiology (Bethesda, Md. : 1985) PMID: 21565989