Wednesday, March 26, 2014

How The FTO Gene Affects Body Weight

sharma-obesity-dna_molecule9Body 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.

Edmonton, AB
ResearchBlogging.orgSmemo 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 (2014). Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature, 507 (7492), 371-5 PMID: 24646999

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Friday, March 7, 2014

Leipzig Forging Its Way As Leaders in Obesity Research

Seal Faculty of Medicine, University of Leipzig, GermanyThis 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.

Leipzig, Germany

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Wednesday, December 11, 2013

Are There Merits To Subtyping Obesity?

sharma-obesity-etiological-approach1Regular 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).

Thus, while ‘subtyping’ of obesity at the molecular or genetic level (as suggested by the authors), may well be of interest, there are already clinically meaningful ways to subtype obese individuals both with regard to etiology and clinical risk.

Nevertheless, the authors are certainly correct in their statement that,

“Obesity is a heterogeneous and complex disease influenced by exogenous and endogenous exposures. Stratifying obesity into meaningful subtypes could provide a better understanding its causes and enable the design and delivery of more effective prevention and treatment interventions.”

It is good to see “mainstream” thinking on this issue finally catching up with this concept.

Berlin, Germany

ResearchBlogging.orgField AE, Camargo CA Jr, & Ogino S (2013). The merits of subtyping obesity: one size does not fit all. JAMA : the journal of the American Medical Association, 310 (20), 2147-8 PMID: 24189835



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Wednesday, July 17, 2013

Transgenerational Metabolic Effects of Maternal Food Intake in Fruit Flies

sharma-obesity-drosophila1Regular 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.

Edmonton, AB

ResearchBlogging.orgMatzkin 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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Friday, June 7, 2013

Bariatric Surgery on Moms Changes Genes in their Kids

sharma-obesity-pregnancy5Regular readers may recall a previous post describing the finding that bariatric surgery on obese women quite dramatically reduces the risk of subsequent obesity in their offspring.

Now, the same group of investigators from Laval University, Quebec City, in a paper published in PNAS, demonstrates striking differences in the methylation of genes controlling glucose metabolism in offspring born to mothers after they underwent gastrointestinal bypass surgery.

In a rather unique set up, the researchers compared gene methylation between a sibling cohort of 25 offspring (age 2-15) born before the mothers underwent bariatric surgery to 25 offspring born to the same mothers after they had surgery.

Almost 6,000 genes were found to be differentially methylated between the “before” and “after” siblings, especially genes known to be involved in glucoregulatory, inflammatory, and vascular disease.

Significant correlations were found between gene methylation levels and gene expression and plasma markers of insulin resistance and metabolic improvements in post-surgical offspring.

As the authors note, this rather unique clinical study shows that bariatric surgery on obese women can have long-lasting (lifelong?) genetic effects on their offspring making them far less prone to obesity and metabolic disease compared to their siblings born to the very same moms prior to surgery.

Not only does this study point to the importance of gestational roots of childhood obesity but also provides robust evidence to the discard the often held view that the current childhood obesity (of for that matter even obesity in young adults) cannot be explained by genetic changes in the population – clearly THE GENES HAVE CHANGED!

Thankfully, as shown in this study, they can be changed back – not by intervening on the kids – but by intervening on the moms even before they become pregnant.

Toronto, AB

Big call out to my youngest daughter, who graduated yesterday from the midwifery program at Ryerson University, Toronto – so proud of you!

ResearchBlogging.orgGuénard F, Deshaies Y, Cianflone K, Kral JG, Marceau P, & Vohl MC (2013). Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery. Proceedings of the National Academy of Sciences of the United States of America PMID: 23716672


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In The News

Diabetics in most need of bariatric surgery, university study finds

Oct. 18, 2013 – Ottawa Citizen: "Encouraging more men to consider bariatric surgery is also important, since it's the best treatment and can stop diabetic patients from needing insulin, said Dr. Arya Sharma, chair in obesity research and management at the University of Alberta." Read article

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