Obesity Is Highly Heritable – But Exactly How This Works Remains Mysterious
One of the most fascinating aspects of obesity is that it is virtually as heritable as body height. Yet, the hunt for the genes that determine body weight has been slow and we are probably not all that much closer to fully understanding exactly how genes influence body weight, than we were 20 years ago, when I myself was dabbling in genetic studies of complex diseases. An article by the science writer Cassandra Willyard from Madison, Wisconsin, published in the Nature Outlook Supplement on Obesity does a valiant job of explaining where we currently stand in our understanding of the genetics of obesity. The article discusses the contribution of genome-wide association studies (GWAS), which have linked about 75 genetic variants have to obesity. “But GWAS studies aren’t perfect. They can lead researchers to important parts of the genome, but it can be difficult to sort out which gene within that region might be the culprit.” Indeed, it appears that the conventional notion that much of the heritability of obesity would be explained by common genetic variants may be wrong. Another possibility could well be that current GWAS studies don’t gene-environment interactions into account. Genes that influence body weight only under certain conditions, cannot be identified in the current studies as environmental exposure of individuals has not been well characterized in these studies. “To resolve the issue, more than a hundred researchers launched a meta-analysis that included 45 studies involving more than 218,000 adults and 19,000 children. Not surprisingly, they found that people who carry the susceptibility gene had a higher risk of obesity. However, the researchers also observed that the risk appears to be reduced in people who are physically active.” Another possibility may well be that obesity is not determined by common variants but rather by a large number of rare variants in the population (present in less than 5% of individuals, i.e. below the threshold of GWAS analyses). The article also describes the additional complexity added by the recent work on epigenetics which, of e.g. …”suggest that what happens in the womb can cause lasting changes in gene expression and influence disease risk even in adulthood, a concept known as fetal programming. This raises the possibility that a mother’s experiences during pregnancy — such as malnutrition — can influence the next generation.” “The epigenetics of obesity isn’t only about the mother — the father’s experiences can have an… Read More »
How The FTO Gene Affects Body Weight
Body weight is one of the most heritable of physiological traits – in fact (believe it or not), it is just as heritable as body height. Among the many genes associated with body weight, data for the FTO gene have been most consistent. But these finding have puzzled researchers, as genetic manipulations of the coding regions of the FTO gene have large effects on body weight, without any apparent change in the function of this gene. Now, a paper by Scott Smemo and colleagues, published in NATURE, suggests a mechanism for how variants of the FTO gene may affect body composition. The answer lies in the way that the region of the FTO gene associated with obesity directly interacts with another gene IRX3, located a few megabases away on the same chromosome. This interaction appears conserved across species all the way back to the zebrafish. Consistent with this finding, it turns out that the obesity-associated single nucleotide polymorphisms of the FTO gene are associated with changes in the expression of IRX3, but not FTO, in human brains. Also consistent with this idea is the fact that IRX3-deficient mice have a 30% lower body weight, primarily due to less fat mass and an increase in basal metabolic rate with browning of white adipose tissue. The animals also appear resistant to the effects of a high-fat diet and appear protected against diabetes. Furthermore, expression of a dominant-negative form of IRX3 in the hypothalamus reproduces the metabolic phenotypes of Irx3-deficient mice. Thus, these findings suggest that FTO exerts its effect on body weight through its functional impact on the IRX3 gene, a gene that has so far not been linked to body weight regulation. This is of particular significance, as IRX3 appears to be a “master gene” that controls the expression of other genes in many tissues including the brain and fat cells. Given that variants of the FTO gene are frequent in the population and consistently linked to obesity (and type 2 diabetes), these findings may take us one step closer to a molecular target for anti-obesity interventions. @DrSharma Edmonton, AB Smemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gómez-Marín C, Aneas I, Credidio FL, Sobreira DR, Wasserman NF, Lee JH, Puviindran V, Tam D, Shen M, Son JE, Vakili NA, Sung HK, Naranjo S, Acemel RD, Manzanares M, Nagy A, Cox NJ, Hui CC, Gomez-Skarmeta JL, & Nóbrega MA… Read More »
Leipzig Forging Its Way As Leaders in Obesity Research
This week, for the 5th consecutive year, I have had the privilege of participating in an extensive review of the obesity research program at the University of Leipzig. I believe that it is fair to say, that starting from scratch, this centre has certainly shown a most remarkable growth and advancement in both fundamental and clinical aspects of obesity research. It is indeed an honour to have had the opportunity to help evaluate and guide this world-class research program over the past five years. It is particularly heartwarming to see how much emphasis this program has placed on supporting the career development of the next generation of obesity researchers in Germany. As the program goes into the renewal phase for hopefully acquiring funding for the next five years, here is a link to past posts on their achievements. @DrSharma Leipzig, Germany
Are There Merits To Subtyping Obesity?
Regular readers may recall that several years ago we proposed that it was time to move beyond considering obesity a homogeneous entity (as defined by BMI alone) and suggested that clinicians may be better off using an “etiological framework” for assessing and addressing the diversity of factors that drive weight gain. This notion, that obesity is not a homogeneous condition, is something other researchers are now slowly catching up with. One example of how “mainstream” thinking is gradually embracing the concept of heterogeneity in obesity is a recent paper by Allison Field and colleagues from Harvard Medical School published in JAMA. In this paper the authors state that, “One reason for the lack of stronger associations with risk factors or more consistently successful treatment is that all types of overweight and obesity are often grouped together. This approach potentially obscures strong associations between risk factors and specific subtypes of obesity.” This is a problem that we have long lamented and regular readers will be well aware that this was the very basis for developing the Edmonton Obesity Staging System (EOSS) as a way to classify obese patients based on how “sick” they are rather than just on how “big” they are. While the authors of this paper may yet have to familiarize themselves with the literature on this issue, there is certainly no reason to expect why individuals with higher EOSS stages will not be the ones to benefit more from obesity interventions than those in the low-risk groups. Depite making a few good points about advances in molecular epidemiology, this article lacks sharp thinking in that it does not clearly distinguish between “etiological” and “phenotypic” heterogeneity of obesity. While the former applies to the many drivers of obesity (which we have categorized as predominantly affecting metabolism, ingestive behaviour and/or physical activity), the latter applies to the many consequences of obesity (which we have categorized as affecting physical, mental and functional health). As we have previously pointed out, the two are not necessarily related. Thus, two individuals, gaining weight for entirely different reasons (e.g. food insecurity vs. binge-eating syndrome), may well present with exactly the same amount of excess body fat and identical clinical complications (e.g. diabetes, reflux disease and urinary incontinence). On the other hand, two individuals, gaining weight for exactly the same reason (e.g. on anti-psychotic medications), may present with quite different complications (e.g. sleep apnea vs. osteoarthritis).… Read More »
Transgenerational Metabolic Effects of Maternal Food Intake in Fruit Flies
Regular readers will be well aware of the accumulating epidemiological, clinical and experimental data showing that maternal dietary habits before and during pregnancy can “permanently” modify their offspring’s metabolism and risk for condition like obesity through epigenetic “reprogramming”. The major implication of these findings are that much of the childhood obesity epidemic can perhaps be explained by the increasing adiposity and older age of present day mothers – a trend that has been well underway for decades. This ability to genetically reprogram metabolism within the space of a single generation appears to be firmly engrained in our biology and dates back to the earliest developmental characteristics of even the most genetically distant species. Thus, a paper by Luciano Matzkin and colleagues, published in PLOS One, shows that peradult parental diet can affect offspring development and metabolism even in the fruit fly (drosophila melanogaster). In their study, the researchers not only found that adult fruit flies emerging from larvae reared on isocaloric diets differing in their amounts of protein relative to sugar show differences in development times and metabolism, but that these alterations are passed on to their offspring, even when these are eating a normal diet. Interestingly, there appeared to be additional genetic effects on how much of these epigenetic changes were transferred to the offspring, suggesting another level of complexity in this relationship. Be that as it may, the evidence is clear that trans-generational metabolic reprogramming can occur within a single generation thus challenging the common view that genes cannot possibly play a role in the current obesity epidemic. Anyone arguing that it would take 100s or 1000s of years for our genes to have changed enough to explain the onset of the obesity epidemic over the past few decades, is simply underestimating both the speed and impact of genetic changes that can occur within a single generation. On a positive side, there is now at least some data suggesting that such changes may be avoided through interventions that promote healthier diets, exercise and limit excess weight gain during pregnancy. This may yet be our best bet in reducing the incidence of childhood obesity. @DrSharma Edmonton, AB Matzkin LM, Johnson S, Paight C, & Markow TA (2013). Preadult parental diet affects offspring development and metabolism in Drosophila melanogaster. PloS one, 8 (3) PMID: 23555695 .
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