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  1. For anyone who’s looked into and reasearched the health effects of different omega-6 containing vegetable oils, you’ll quickly find that there’s a strong connection between all of them and the major degenerative diseases such as diabetes, cancer, heart disease, alzheimer’s and even obesity. Here are a couple of excerpts from the full text studies that I found particularily interesting: On obesity from https://www.ncbi.nlm.nih.gov/pubmed/23249760: ‘Recent studies have emphasized the proadipogenic properties of the omega-6 PUFA, and provided evidence that rodents fed on diets with omega-6 PUFA contents similar to the typical US diet (6–8% energy) have an increased fat mass. Importantly, recent studies have shown that perinatal exposure to a high omega-6 PUFA diet results in a progressive accumulation of body fat across generations.’ On chronic disease from https://www.ncbi.nlm.nih.gov/pubmed/18408140: ‘Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today’s Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases...’ On chronic disease from https://www.ncbi.nlm.nih.gov/pubmed/22570770: ‘...high intake of n-6 PUFA, along with low intakes of n-3 PUFA, shifts the physiological state to one that is proinflammatory and prothrombotic with increases in vasospasm, vasoconstriction, and blood viscosity and the development of diseases associated with these conditions.’ So if you HAVE to cook with oil (which I don’ t recommend) using something like MCT oil or adding olive oil to salad might be less harmful compared to n-6 oils. Even then, fats in general, also those in olive oil have been connected to diabetes and MCT oil/coconut oil has some pretty potent cholesterol raising effects. This is certainly common knowledge around here but I find that researching these connections on my own gives me a more complete understanding rather than just taking somebody’s word for it. I find it’s also easier to stay on a diet and avoid the harmful foods if you are constantly reading studies and seeing evidence everywhere on their negative effects yourself. If you have more reaserch to add, I’d appreciate it.
  2. Dean Pomerleau

    The Calorie Controversy

    All, There is a good article out today in the Atlantic on just how difficult it is to accurately calculate the energy value available from food. It talks about how the USDA does it, and how it varies from food-to-food (e.g. almonds & walnuts provide 20-33% fewer calories than expected), and person-to-person depending on one's genetics and microbiome. It talks about eating for satiety rather than targeting a certain calorie level is likely to be more effective for regular people trying to lose weight. Here is a passage I found quite interesting, given my advocacy of fruit: Since 2005, David Wishart of the University of Alberta has been cataloguing the hundreds of thousands of chemical compounds in our bodies, which make up what’s known as the human metabolome... According to Wishart, these chemicals and their interactions affect energy balance. He points to research demonstrating that high-fructose corn syrup and other forms of added fructose (as opposed to fructose found in fruit) can trigger the creation of compounds that lead us to form an excess of fat cells, unrelated to additional calorie consumption. “If we cut back on some of these things,” he says, “it seems to revert our body back to more appropriate, arguably less efficient metabolism, so that we aren’t accumulating fat cells in our body. An interesting article worth reading in its entirety. --Dean
  3. All, You may have seen the recent story in the popular press about the possibility of "mysterious" causes of the obesity epidemic with titles like: Obesity is about More than Diet and Exercise: Why It’s Harder to Stay Healthier Now More Than Ever and: Not mom's weight loss: For millennials, more than diet and exercise at play Here is the sensational way the reporter in the first story describes it: According to research, a person with the same diet and exercise habits in the 80s would have a 2.3 point increase in their BMI in 2006 without changing anything at all — simply by existing 30 years in the future. That’s right — existing in our modern environment has contributed to a greater body mass among the population. Wow - that sounds bizarre, scary, and oddly comforting at the same time. Maybe it's not our lifestyle choices that are making us fat, so maybe it's not our fault. I've got to read more! ... They are reporting on a new study [1] that they (and the authors, to some degree) claim shows that over the last 30 years Americans have gotten fatter for reasons other than eating too much food and/or engaging in too little physical activity. The reporters speculate about a range of causes, including: We are more stressed and sleep less. We are exposed to more pesticides and industrial chemicals. Because of our changing diet we have less healthy gut microbiomes. We take more medications associated with weight gain than we used to, such as antidepressants. We increasingly live in climate-controlled worlds that don't require us to burn calories to maintain our body temperature. So I decided to look at the actual study to see if it is sound, and what the authors actually said. The paper [1] analyzed the NHANES data from 1971 to 2008, in which every few years researchers went to the homes of about 3000 Americans (men and women) to take measurements (e.g. height and weight) and ask them questions about their diet and lifestyle. Here is the key table from the paper showing how the various measures changed over the years (note - they are interviewing different people every few years, this isn't a longitudinal study in which they follow the same people over time): The first thing they observed is that BMI has gone up about 10% (3 units) in both men and women since the early '70s - the population has obviously gotten fatter. They also observed that self-reported calorie intake has gone up by 10-14% over that same period. So people are eating more, and getting (nearly proportionally) fatter - where is the discrepancy? The authors say that self-reported leisure time physical activity (PA) rose by 47% and 120% in men and women, respectively, over the latter part of the time period (physical activity wasn't recorded prior to 1980 in the NHANES protocol). So, the authors conclude, if people say they are only eating 10-14% more, and are exercising a ton more, their weight shouldn't have gone up by 10%, so something else besides diet and exercise must explain their weight gain. No potential flaws in this logic, no siree ... Seriously. The NHANES data was interviewing different people, using different questioning techniques and different questions over the years. In NHANES I (1971—1975) and NHANES II (1976—1980), in-person interviews were used to obtain self-reported dietary information via a 24- h dietary recall questionnaire that assessed food and beverage intake for weekdays only. In NHANES III (1988—1994), dietary information was obtained through a self-reported 24-h dietary recall using a computer-assisted, automated, interactive method for any day of the week. In NHANES 1999—2002, a multiple-pass computer-assisted dietary interview format was used to collect detailed self-reported information about all foods and beverages that were consumed the day prior to the in-person interview (weekday or weekend). In NHANES 2003—2008, 24-h self-reported dietary recalls were performed twice (3—10 days apart) using an automated multiple pass method. Right off the bat, people may have been more reluctant fudge the numbers on what / how much they ate during the face-to-face in-person interviews from 1971-1980, relative to the impersonal computer-based data collection used after 1980, which could easily have resulted in subjects underestimating calorie intake during the later years. Plus, it's well known that self-reported diet recall is a crappy source of information about what people actually eat. More importantly, the heavier people are, the more likely they are to underreport how much they eat, and overreport how much physical activity they engage in. So as people got fatter over the years, the "mystery" of why they are gaining weight when not eating that much more, while exercising a lot more, may simply be that they lie more about their eating and exercise habits as they get fatter. In fact, the authors suggest this effect as the first possible explanation for their findings: Whether self-reported dietary intake accurately reflects an individual’s true dietary intake has been questioned [34]. Indeed, doubly-labelled water studies typically show that individuals underreport their energy intake, and that the magnitude of the underreporting may be larger in people who are obese [35]. <snip> This finding is in line with those of several other studies in which individuals with obesity reported consuming similar or fewer daily calories than those who are normal weight [7,11]. While this has frequently been attributed to underreporting [19,20], several additional possible explanations must be considered... The authors then go on to speculate about a few of the 'mystery' causes of weight gain mentioned in the popular reports and listed above. This seem to me to be a clear case of the authors of the study, and especially the reporters writing about the study, downplaying the most likely explanations (i.e. under/over reporting of diet and exercise by the obese, changes in protocol skewing results) in favor of speculative explanations that appeal to people's desire to avoid personal responsibility for their weight gain, e.g. "it isn't your fault - you've gained weight because of the mysterious obesity-promoting chemicals in our food or environment these days". To be fair, the second (CNN) article linked above does acknowledge at the end the possibility that the explanation could be a mundane combination of misremembering and/or intentional underreporting. But it nonetheless stresses the significance of mysterious causes, likely to gain more eyeballs for their story. Pretty sad... Note: I'm not saying (definitively) that these other possible factors haven't contributed at all to the recent dramatic weight gain among the American population. All I'm saying is that this study provides extremely weak evidence to support such speculations, and that the mundane explanation of a positive energy balance due to eating too much and exercising too little is likely the cause of the vast majority of the observed weight gain. --Dean ---------- [1] Obes Res Clin Pract. 2015 Sep 14. pii: S1871-403X(15)00121-0. doi: 10.1016/j.orcp.2015.08.007. [Epub ahead of print] Secular differences in the association between caloric intake, macronutrient intake, and physical activity with obesity. Brown RE(1), Sharma AM(2), Ardern CI(1), Mirdamadi P(1), Mirdamadi P(1), Kuk JL(3). Full Text: http://www.obesityresearchclinicalpractice.com/article/S1871-403X(15)00121-0/pdf BACKGROUND: To determine whether the relationship between caloric intake, macronutrient intake, and physical activity with obesity has changed over time. METHODS: Dietary data from 36,377 U.S. adults from the National Health and Nutrition Survey (NHANES) between 1971 and 2008 was used. Physical activity frequency data was only available in 14,419 adults between 1988 and 2006. Generalised linear models were used to examine if the association between total caloric intake, percent dietary macronutrient intake and physical activity with body mass index (BMI) was different over time. RESULTS: Between 1971 and 2008, BMI, total caloric intake and carbohydrate intake increased 10-14%, and fat and protein intake decreased 5-9%. Between 1988 and 2006, frequency of leisure time physical activity increased 47-120%. However, for a given amount of caloric intake, macronutrient intake or leisure time physical activity, the predicted BMI was up to 2.3kg/m(2) higher in 2006 that in 1988 in the mutually adjusted model (P<0.05). CONCLUSIONS: Factors other than diet and physical activity may be contributing to the increase in BMI over time. Further research is necessary to identify these factors and to determine the mechanisms through which they affect body weight. PMID: 26383959
  4. All, There is a new study [1] out this week getting lots of media attention with headlines like Study: Obesity more dangerous to health than lack of fitness and 'Fat but fit' counts for nothing scientists say. After reading the full text (via sci-hub.io) it appears this is a gross oversimplification, if not outright distortion of what the study really says. In the study, researchers looked at the aerobic fitness and weight of 1.3 million Swedish men at the time of their military conscription (mean age 18). Aerobic fitness was tested by seeing how long the men could keep pedalling on a stationary bike whose resistance was increased at a rate of 2.5 watts/min. The subjects were then followed for an average of 29 years (to around age 47 - so still relatively young), during which 44K of them died. They then compiled statistics about mortality rate as a function of both baseline weight and baseline aerobic fitness. The results of the entire study are nicely summarized in a single graph (don't you love it when that happens?!). Here it is: There are several interesting things that can be gleaned from this graph: Being more aerobically fit resulted in reduced mortality across all four BMI categories. There was virtually no difference in the mortality rate of men with low BMI (< 18.5) vs. normal BMI (18.5 - 25). The fact that the researchers did not correct for smoking would seem to make this lack of difference even more significant, since it is likely that the skinny group smoked more than the normal weight group, and so would be expected to have a higher mortality rate, based on many other studies. The most fit obese men were significantly more likely to die than the least fit normal or even overweight individuals. It is only the last of these three points which seem to have sparked all the media attention. But as you can see, the study has much more interesting information than just that, particularly for us CR practitioners - namely that when it comes to reducing mid-life mortality, being skinny isn't bad and being more aerobically fit is good. --Dean --------- [1] International Journal of Epidemiology, 2015, 1–10 doi: 10.1093/ije/dyv321 Aerobic fitness in late adolescence and the risk of early death: a prospective cohort study of 1.3 million Swedish men Gabriel Hogstrom, Anna Nordstrom and Peter Nordstrom Full text (via sci-hub.io): http://ije.oxfordjournals.org.sci-hub.io/content/early/2015/12/20/ije.dyv321.full Abstract Background: Fitness level and obesity have been associated with death in older populations. We investigated the relationship between aerobic fitness in late adolescence and early death, and whether a high fitness level can compensate the risk of being obese. Methods: The cohort comprised 1 317 713 Swedish men (mean age, 18 years) that conscripted between 1969 and 1996. Aerobic fitness was assessed by an electrically braked cycle test. All-cause and specific causes of death were tracked using national registers. Multivariable adjusted associations were tested using Cox regression models. Results: During a mean follow-up period of 29 years, 44 301 subjects died. Individuals in the highest fifth of aerobic fitness were at lower risk of death from any cause [hazard ratio (HR), 0.49; 95% confidence interval (CI), 0.47–0.51] in comparison with individuals in the lowest fifth, with the strongest association seen for death related to alcohol and narcotics abuse (HR, 0.20; 95% CI, 0.15–0.26). Similar risks were found for weight-adjusted aerobic fitness. Aerobic fitness was associated with a reduced risk of death from any cause in normalweight and overweight individuals, whereas the benefits were reduced in obese individuals (P< 0.001 for interaction). Furthermore, unfit normal-weight individuals had 30% lower risk of death from any cause (HR, 0.70; 95% CI, 0.53–0.92) than did fit obese individuals. Conclusions: Low aerobic fitness in late adolescence is associated with an increased risk of early death. Furthermore, the risk of early death was higher in fit obese individuals than in unfit normal-weight individuals. Key words: Fitness, obesity, death PMID: 26686843
  5. Al posted a new study [1], that appears to me to support the theory I've been promulgating for a while that what's important for health and longevity is the quality of one's diet and lifestyle, rather than the quantity of calories one eats. The study followed over 90,000 postmenopausal women for about 13 years to see how the baseline quality of their diet (as quantified by 4 popular dietary quality metrics) impacted subsequent mortality. The dietary quality metrics were designed to gauge how well the women adhered to commonly-accepted 'good' dietary patterns, like following a Mediterranean Diet, or a DASH-like diet. All four shared much in common (emphasize fruits & vegetables, whole grains, avoid red & processed meat, etc.), and fortunately all four resulted in similar outcomes in this study, so I'll collapse all four in my brief discussion of the results below into a single notion of a "good diet". What they found was the women who had the best diet (i.e. were in the highest quintile of 'good diet' score relative to lowest quintile) had about a 20-25% lower risk of dying during the 13 year follow-up period. They also had a lower BMI (25-26 vs. 28-29) although weren't especially slim, and the exercised more than the women who ate the crappiest diet, although the researchers attempted to factor out BMI, exercise, and calories (see next point) from their statistical analysis to focus on the link between diet quality and mortality. On average the women who were eating the best diet and hence were healthier & longer-lived didn't report eating any fewer calories than the women eating the crappiest diet (although as we know food frequency questionnaires are fraught with difficulties...), they were just eating healthy foods rather than unhealthy ones. In short, this is yet one more study showing that dramatic improvements in health/longevity, on par with what we hope to achieve via CR, seem to be attainable by following a healthy obesity-avoiding diet & lifestyle, but without calorie restriction. --Dean -------- [1] Comparing indices of diet quality with chronic disease mortality risk in postmenopausal women in the Women's Health Initiative Observational Study: evidence to inform national dietary guidance. George SM, Ballard-Barbash R, Manson JE, Reedy J, Shikany JM, Subar AF, Tinker LF, Vitolins M, Neuhouser ML. Am J Epidemiol. 2014 Sep 15;180(6):616-25. doi: 10.1093/aje/kwu173. Epub 2014 Jul 17. PMID: 25035143 Free PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157698/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157698/pdf/kwu173.pdf Abstract Poor diet quality is thought to be a leading risk factor for years of life lost. We examined how scores on 4 commonly used diet quality indices-the Healthy Eating Index 2010 (HEI), the Alternative Healthy Eating Index 2010 (AHEI), the Alternate Mediterranean Diet (aMED), and the Dietary Approaches to Stop Hypertension (DASH)-are related to the risks of death from all causes, cardiovascular disease (CVD), and cancer among postmenopausal women. Our prospective cohort study included 63,805 participants in the Women's Health Initiative Observational Study (from 1993-2010) who completed a food frequency questionnaire at enrollment. Cox proportional hazards models were fit using person-years as the underlying time metric. We estimated multivariate hazard ratios and 95% confidence intervals for death associated with increasing quintiles of diet quality index scores. During 12.9 years of follow-up, 5,692 deaths occurred, including 1,483 from CVD and 2,384 from cancer. Across indices and after adjustment for multiple covariates, having better diet quality (as assessed by HEI, AHEI, aMED, and DASH scores) was associated with statistically significant 18%-26% lower all-cause and CVD mortality risk. Higher HEI, aMED, and DASH (but not AHEI) scores were associated with a statistically significant 20%-23% lower risk of cancer death. These results suggest that postmenopausal women consuming a diet in line with a priori diet quality indices have a lower risk of death from chronic disease. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US. KEYWORDS: diet; diet quality indices; mortality risk; postmenopausal women; prospective cohort study
  6. All, Obesity researcher Dr. Robert Lustig, who is notorious for placing blame for the obesity epidemic on added sugar, especially fructose, has a new paper out [1] that is getting quite a bit of popular press attention on the link between added sugar/fructose in the diet of kids and obesity / metabolic syndrome. Despite my distrust of Lustig and his "one underlying cause" thesis, believing as I do that many factors contribute to obesity, including 'mysterious' factors (see this thread), this was nevertheless a pretty interesting study. He recruited ~40 obese kids suffering from metabolic syndrome and for 9 days had them eat a crappy diet with less added sugar/fructose than their normal crappy diet, keeping macronutrients the same, and measured how their markers for metabolic syndrome changed. More specifically, at baseline these kids were on average eating 28% of daily calories from (presumably added) sugar, with 12% of it from (presumably added) fructose. Given where added sugar comes from in general in our culture, they were most likely eating a lot of sugar sweetened beverages, pastries, desserts and candy. In place of these, the authors substituted "kid-friendly" foods with less added sugar, which at one point in the paper they characterize as: This “child-friendly” study diet included various no- or low-sugar added processed foods including turkey hot dogs, pizza, bean burrritos, baked potato chips, and popcorn that were purchased at local supermarkets. Strangely, elsewhere in the paper the authors characterize the intervention diet in a way that sounds significantly less crappy: The menu was planned to restrict added sugar, while substituting other carbohydrates such as those in fruit, bagels, cereal, pasta, and bread so that the percentage of calories consumed from carbohydrate was consistent with their baseline diet, but total dietary sugar and fructose were reduced... A diet enriched with "fruit, bagels, cereal, pasta, and bread" compared with their baseline diet (likely consisting of lots of soda, cookies and candy) sounds like a pretty big improvement to me, although fiber was only increased from 9g at baseline to 11g during the study, so it apparently wasn't that big an improvement. But digging a little further, the second set of substitution foods (fruit, bagels, cereal, pasta, and bread) sounds a lot more plausible to me than the first set (turkey hot dogs, pizza, bean burritos, baked potato chips, and popcorn), given that elsewhere the authors state that: ...compared with the baseline macronutrient distribution determined by FFQ, the total percentage of carbohydrate intake on the study diet decreased by 4%, protein increased by 2%, and there was no change in percentage calories from fat. Substituting fat- and protein-laden processed foods in first set (pizza, bean burritos, baked potato chips etc) for sugary foods and soda, would not have left macronutrients virtually unchanged, as the authors claim. But substituting the high carb foods with little added sugar from the second set (fruit, bagels, cereal, pasta, and bread), would have left macronutrients nearly the same but reduced added sugar, as the authors claim. So if the substitutions were "fruit, bagels, cereal, pasta, and bread" for soda, pastry, and candy, perhaps the the intervention diet wasn't as crappy as Lustig claims, and that the popular press articles like the Wall Street Journal story are parroting: Researchers from the University of California, San Francisco, and Touro University California took soda, pastries, sugary cereals and other foods and beverages sweetened with added sugar away from 43 Latino and African-American children and teens for nine days. They replaced those foods with pizza, baked potato chips, and other starchy processed foods. Either way, it is a rather important ambiguity for the authors to not only leave open, but in fact bake right into the report on their study through the conflicting descriptions of the intervention diet. Since they gave the kids all their food during the intervention period, you would think they would have documented the details of the intervention diet in the paper (or at least in the supplemental material - which doesn't appear to exist), but apparently not. That's Lustig for you... Given all that, what they found was that after 10 days, most indicators of metabolic syndrome improved significantly relative to baseline, including fasting glucose, insulin, OGTT, and blood lipids. They tried to maintain calories and avoid weight loss to make for a fair comparison, but on average the kids lost a couple pounds, which could account for some of the improvement. They separately analysed data from the kids who didn't lose weight, and found that the results weren't quite as strong, but many of the measures still improved, independent of weight loss. So overall, this study seems to provide some (albeit relatively weak) support for the hypothesis that added sugar and fructose are particularly detrimental, and increase risk of metabolic syndrome. --Dean ----------- [1] Lustig, R. H., Mulligan, K., Noworolski, S. M., Tai, V. W., Wen, M. J., Erkin-Cakmak, A., Gugliucci, A. and Schwarz, J.-M. (2015), Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome. Obesity. doi: 10.1002/oby.21371 Free Full Text: http://onlinelibrary.wiley.com/doi/10.1002/oby.21371/full Abstract Objective Dietary fructose is implicated in metabolic syndrome, but intervention studies are confounded by positive caloric balance, changes in adiposity, or artifactually high amounts. This study determined whether isocaloric substitution of starch for sugar would improve metabolic parameters in Latino (n = 27) and African-American (n = 16) children with obesity and metabolic syndrome. Methods Participants consumed a diet for 9 days to deliver comparable percentages of protein, fat, and carbohydrate as their self-reported diet; however, dietary sugar was reduced from 28% to 10% and substituted with starch. Participants recorded daily weights, with calories adjusted for weight maintenance. Participants underwent dual-energy X-ray absorptiometry and oral glucose tolerance testing on Days 0 and 10. Biochemical analyses were controlled for weight change by repeated measures ANCOVA. Results Reductions in diastolic blood pressure (−5 mmHg; P = 0.002), lactate (−0.3 mmol/L; P < 0.001), triglyceride, and LDL-cholesterol (−46% and −0.3 mmol/L; P < 0.001) were noted. Glucose tolerance and hyperinsulinemia improved (P < 0.001). Weight reduced by 0.9 ± 0.2 kg (P < 0.001) and fat-free mass by 0.6 kg (P = 0.04). Post hoc sensitivity analysis demonstrates that results in the subcohort that did not lose weight (n = 10) were directionally consistent. Conclusions Isocaloric fructose restriction improved surrogate metabolic parameters in children with obesity and metabolic syndrome irrespective of weight change.
  7. Dean Pomerleau

    Genetics of Obesity

    There is an new study on the link between genetics and obesity reported on in this popular press article: http://www.huffingtonpost.com/entry/obesity-gene-discovery-could-forever-change-weight-loss_55d4f994e4b0ab468d9fc0f4 Study [1] is the (rather technical) abstract for the paper associated with the story. I'll do my best to summarize the background and the findings of this study, which I found really interesting. First a little background. It has been known for a while that a particular gene on chromosome 16 named FTO has many (over 200) SNPs (single nucleotide polymorphisms - i.e. common variations in particular base pairs along this gene), several of which appear to be associated with obesity. Here are two older studies [2][3] that address this linkage. Study [2] focused on SNP rs9939609. It found that people who carry one (or especially two) copies of the 'obese' allele ('A') for this SNP were significantly more likely to be obese than those who carry the 'lean' variant ('T'). Study [3] found the same thing for three other FTO SNPs, rs1421085, rs17817449 and rs8043757. It found that people with the 'obese' variants for these three SNPs ('C', 'G' and 'T', respectively) were about 2.5 times more likely to be obese than those who had the lean variants for these three SNPs ('T', 'T', 'A', respectively). The newest study [1], focused on the first of the three SNPs from [3], namely SNP rs1421085, and did something really cool and cutting edge. They took fat cells from mice and humans and used the recently-developed CRISPR gene editing technique to change this particular SNP from the 'obese' variant ('C') to the 'lean' variant ('T'), and then observed what happened to the cells. What they found was that the fat cells converted from being thermogenically active, 'beige' fat cells (i.e. like brown fat cells) to 'white' fat cells that are much more efficient at storing fat, rather than burning it. This can be spun as a nice mechanistic story to explain why at least this SNP is associated with obesity. People who have 'C' for rs1421085 produce more white fat cells, making them more efficient at storing fat - i.e. they have a more 'thrifty' genotype and will therefore (presumably) store more fat for a given calorie intake. Now comes the interesting citizen science part. Data on all four of obesity-related SNPs mentioned above are available to subscribers of 23andMe. Simply log in, then go to this page: https://www.23andme.com/you/explorer/gene/?gene_name=FTO to get a list of all 200+ SNPs from the FTO gene that 23andMe sequences, and search on the page for these four SNPs. Here are my results: rs9939609 TT (lean variant = T) rs1421085 TT (lean variant = T) rs17817449 TT (lean variant = T) rs8043757 AA (lean variant = A) As you can see, I've inherited two copies (one from each of my parents) of the 'lean' allele for each of these four SNPs. So it is no wonder that unintended weight gain has never been an problem for me - at least according to these SNPs I have the antithesis of the 'thrifty genotype'. I'm curious what other CRONies who are also subscribers to 23andMe have for these SNPs, and whether they consider themselves to have a 'thrifty genotype' (easily gain weight) or not. I also wonder whether long-term success on a CR lifestyle is in any way correlated with the values for these SNPs. There is some indication [4] that some of the FTO SNPs (including rs9939609) have an effect on energy intake and preference for energy dense (i.e. high fat) foods, and from [2] we saw that people with the 'obese' allele for rs9939609 and who eat a high-fat, low-carb diet have a higher BMI, which could discourage people trying to practice CR in order to lose weight. Conversely, having a 'thrifty genotype' might make it easier to maintain a low calorie intake without becoming terribly skinny, which can sometimes result in social pressure to eat more to avoid looking like a concentration camp victim. :) Anyway, I've probably grossly oversimplified the science, but I found it fascinating and would be interested to hear what other 23andMe subscribers have for these alleles. --Dean ------------------------------- [1] N Engl J Med. 2015 Aug 19. [Epub ahead of print] FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. Claussnitzer M(1), Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C, Glunk V, Sousa IS, Beaudry JL, Puviindran V, Abdennur NA, Liu J, Svensson PA, Hsu YH, Drucker DJ, Mellgren G, Hui CC, Hauner H, Kellis M. Background Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. Methods We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples from patients. Results Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. Conclusions Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.). PMID: 26287746 --------------- [2] Br J Nutr. 2012 Nov 28;108(10):1859-65. doi: 10.1017/S0007114511007410. Epub 2012 Jan 23. Association of the fat mass and obesity-associated (FTO) gene variant (rs9939609) with dietary intake in the Finnish Diabetes Prevention Study. Lappalainen T(1), Lindström J, Paananen J, Eriksson JG, Karhunen L, Tuomilehto J, Uusitupa M. A cluster of variants in the fat mass and obesity-associated (FTO) gene are associated with the common form of obesity. Well-documented dietary data are required for identifying how the genetic risk can be modified by dietary factors. The objective of the present study was to investigate the associations between the FTO risk allele (rs9939609) and dietary intake, and to evaluate how dietary intake affects the association between FTO and BMI in the Finnish Diabetes Prevention Study during a mean follow-up of 3·2 years. A total of 479 (BMI >25 kg/m2) men and women were genotyped for rs9939609. The participants completed a 3 d food record at baseline and before every annual study visit. The average intakes at baseline and during the years 1, 2 and 3 were calculated. At baseline, the FTO variant rs9939609 was not associated with the mean values of total energy intake, macronutrients or fibre. At baseline, a higher BMI by the FTO risk genotype was detected especially in those who reported a diet high in fat with mean BMI of 30·6 (sd 4·1), 31·3 (sd 4·6) and 34·5 (sd 6·2) kg/m2 for TT, TA and AA carriers, respectively (P =0·005). Higher BMI was also observed in those who had a diet low in carbohydrates (P =0·028) and fibre (P =0·015). However, in the analyses adjusted for total energy intake, age and sex, significant interactions between FTO and dietary intakes were not found. These findings suggest that the association between the FTO genotype and obesity is influenced by the components of dietary intake, and the current dietary recommendations are particularly beneficial for those who are genetically susceptible for obesity. PMID: 22265018 ----------------------- [3] Gene. 2015 Mar 1;558(1):75-81. doi: 10.1016/j.gene.2014.12.050. Epub 2014 Dec 24. Common variations in the FTO gene and obesity in Thais: a family-based study. Chuenta W(1), Phonrat B(2), Tungtrongchitr A(3), Limwongse C(4), Chongviriyaphan N(5), Santiprabhob J(6), Tungtrongchitr R(7). Several studies have revealed the association between single nucleotide polymorphisms (SNPs) in the first intron of fat mass and obesity-associated (FTO) gene and obesity. To date, more than 100 SNPs in the FTO gene have been identified in various populations. Nevertheless, this association has not yet been confirmed in Thai populations. The aim of this study was to investigate whether FTO variants are associated with obesity in Thais. We analyzed ten variants in the FTO gene (rs9939609, rs9926289, rs8050136, rs9930501, rs9930506, rs9940646, rs9940128, rs1421085, rs17817449, and rs8043757) in 12 families (83 persons); composed of 12 proband cases and 71 associated family members. All participants were genotyped using polymerase chain reaction (PCR) method and DNA sequencing assay. We found significant associations between three SNPs located in the first intron of FTO gene (rs1421085, rs17817449, and rs8043757) and obesity. The odds ratios were 2.82 (95% CI, 1.16-6.90, p=0.02) for rs1421085 and rs17817449, and 3.15 (95% CI, 1.28-7.76, p=0.01) for rs8043757. Strong linkage disequilibrium among ten SNPs was observed (D'>0.8). Haplotype analysis (combination of rs1421085 (T/C), rs17817449 (T/G), and rs8043757 (A/T)) showed that the CGT haplotype is associated with an increased risk of obesity (OR, 2.42; 95% CI, 1.18-4.97; p=0.018) when compared to the reference haplotype (TTA). The SNPs rs1421085, rs17817449 and rs8043757 in the first intron of the FTO gene are associated with increasing risk of obesity in Thais. Copyright © 2014 Elsevier B.V. All rights reserved. PMID: 25542809 [PubMed - indexed for MEDLINE] ------------------ [4] N Engl J Med. 2008 Dec 11;359(24):2558-66. doi: 10.1056/NEJMoa0803839. An obesity-associated FTO gene variant and increased energy intake in children. Cecil JE(1), Tavendale R, Watt P, Hetherington MM, Palmer CN. Author information: (1)Bute Medical School, University of St Andrews, St Andrews, United Kingdom. Comment in N Engl J Med. 2009 Apr 9;360(15):1571-2; author reply 1572. N Engl J Med. 2008 Dec 11;359(24):2603-4. BACKGROUND: Variation in the fat mass and obesity-associated (FTO) gene has provided the most robust associations with common obesity to date. However, the role of FTO variants in modulating specific components of energy balance is unknown. METHODS: We studied 2726 Scottish children, 4 to 10 years of age, who underwent genotyping for FTO variant rs9939609 and were measured for height and weight. A subsample of 97 children was examined for possible association of the FTO variant with adiposity, energy expenditure, and food intake. RESULTS: In the total study group and the subsample, the A allele of rs9939609 was associated with increased weight (P=0.003 and P=0.049, respectively) and body-mass index (P=0.003 and P=0.03, respectively). In the intensively phenotyped subsample, the A allele was also associated with increased fat mass (P=0.01) but not with lean mass. Although total and resting energy expenditures were increased in children with the A allele (P=0.009 and P=0.03, respectively), resting energy expenditure was identical to that predicted for the age and weight of the child, indicating that there is no defect in metabolic adaptation to obesity in persons bearing the risk-associated allele. The A allele was associated with increased energy intake (P=0.006) independently of body weight. In contrast, the weight of food ingested by children who had the allele was similar to that in children who did not have the allele (P=0.82). CONCLUSIONS: The FTO variant that confers a predisposition to obesity does not appear to be involved in the regulation of energy expenditure but may have a role in the control of food intake and food choice, suggesting a link to a hyperphagic phenotype or a preference for energy-dense foods. 2008 Massachusetts Medical Society PMID: 19073975
  8. All, One of the initial motivations for studying the possible benefits of the Omega-3s PUFAs DHA & EPA came from observations that the Inuits of Greenland, whose diet contains a very high proportion of polyunsaturated fat from cold-water fish and marine mammals, suffer from relatively low rates of cardiovascular disease. But randomized control trials of the benefits of DHA / EPA supplements for (primary or secondary) prevention of cardiovascular disease have generally been disappointing (e.g. [1]). This new study [2] in Science, might suggest at least part of the explanation for this apparent paradox. That paper used population-genetic analysis of Greenland Inuits to discover regions of two chromosomes that seem to have experienced strong selection in the recent past. Those regions also happen to contain genes involved in fatty acid metabolism; and the variants of the genes that have increased in frequency in Inuits are also associated with small stature and lower weight. From the abstract: By analyzing membrane lipids, we found that the selected alleles modulate fatty acid composition, which may affect the regulation of growth hormones. Thus, the Inuit have genetic and physiological adaptations to a diet rich in PUFAs. In an accompanying commentary, there is a fascinating map of relatively recent human genetic variations and where they occur around the world (click to enlarge): The one that isn't shown that I find very interesting is the salivary amylase gene (AMY1) for digesting starch. Several studies (e.g. [3]) have found that the number of duplicates of the AMY1 a person has can vary from 2 to about 15 from one individual to the next. The more AMY1 copies you have, the better you are at digesting starch / carbohydrates, and the less prone you are to obesity [3]. Study [4] looked at how the number of AMY1 copies varied between people of different ethnic groups and found a striking correlation between the amount of starch in their ancestral diet and the number of AMY1 copies their genome contained. Here is that result illustrated on a map (click to enlarge): In short, it appears that in cultures whose ancestral diet contained a large fraction of carbohydrates, more copies of the AMY1 gene were selected for since it helped them better process carbs. The bottom line appears to be that there is no "one size fits all" diet that is right for everyone. To some extent at least, the best diet for an individual depends on his/her genes. --Dean -------------------------------- [1] Arch Intern Med. 2012 May 14;172(9):686-94. doi: 10.1001/archinternmed.2012.262. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Kwak SM(1), Myung SK, Lee YJ, Seo HG; Korean Meta-analysis Study Group. Collaborators: Myung SK, Ju W, Oh SW, Bae JH, Kim YK, Park CH, Jeon YJ, Lee EH, Chang YJ, Park SM, Eom CS, Lee YJ, Jung HS, Kwak SM. BACKGROUND: Although previous randomized, double-blind, placebo-controlled trials reported the efficacy of omega-3 fatty acid supplements in the secondary prevention of cardiovascular disease (CVD), the evidence remains inconclusive. Using a meta-analysis, we investigated the efficacy of eicosapentaenoic acid and docosahexaenoic acid in the secondary prevention of CVD. METHODS: We searched PubMed, EMBASE, and the Cochrane Library in April 2011. Two of us independently reviewed and selected eligible randomized controlled trials. RESULTS: Of 1007 articles retrieved, 14 randomized, double-blind, placebo-controlled trials (involving 20 485 patients with a history of CVD) were included in the final analyses. Supplementation with omega-3 fatty acids did not reduce the risk of overall cardiovascular events (relative risk, 0.99; 95% CI, 0.89-1.09), all-cause mortality, sudden cardiac death, myocardial infarction, congestive heart failure, or transient ischemic attack and stroke. There was a small reduction in cardiovascular death (relative risk, 0.91; 95% CI, 0.84-0.99), which disappeared when we excluded a study with major methodological problems. Furthermore, no significant preventive effect was observed in subgroup analyses by the following: country location, inland or coastal geographic area, history of CVD, concomitant medication use, type of placebo material in the trial, methodological quality of the trial, duration of treatment, dosage of eicosapentaenoic acid or docosahexaenoic acid, or use of fish oil supplementation only as treatment. CONCLUSION: Our meta-analysis showed insufficient evidence of a secondary preventive effect of omega-3 fatty acid supplements against overall cardiovascular events among patients with a history of cardiovascular disease. PMID: 22493407 ----------------- [2] Science. 2015 Sep 18;349(6254):1343-1347. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Fumagalli M(1), Moltke I(2), Grarup N(3), Racimo F(4), Bjerregaard P(5), Jørgensen ME(6), Korneliussen TS(7), Gerbault P(8), Skotte L(2), Linneberg A(9), Christensen C(10), Brandslund I(11), Jørgensen T(12), Huerta-Sánchez E(13), Schmidt EB(14), Pedersen O(3), Hansen T(15), Albrechtsen A(16), Nielsen R(17). The indigenous people of Greenland, the Inuit, have lived for a long time in the extreme conditions of the Arctic, including low annual temperatures, and with a specialized diet rich in protein and fatty acids, particularly omega-3 polyunsaturated fatty acids (PUFAs). A scan of Inuit genomes for signatures of adaptation revealed signals at several loci, with the strongest signal located in a cluster of fatty acid desaturases that determine PUFA levels. The selected alleles are associated with multiple metabolic and anthropometric phenotypes and have large effect sizes for weight and height, with the effect on height replicated in Europeans. By analyzing membrane lipids, we found that the selected alleles modulate fatty acid composition, which may affect the regulation of growth hormones. Thus, the Inuit have genetic and physiological adaptations to a diet rich in PUFAs. Copyright © 2015, American Association for the Advancement of Science. PMID: 26383953 ----------------- [3] Nat Genet. 2014 May;46(5):492-7. doi: 10.1038/ng.2939. Epub 2014 Mar 30. Low copy number of the salivary amylase gene predisposes to obesity. Falchi M(1), El-Sayed Moustafa JS(2), Takousis P(3), Pesce F(4), Bonnefond A(5), Andersson-Assarsson JC(6), Sudmant PH(7), Dorajoo R(8), Al-Shafai MN(9), Bottolo L(10), Ozdemir E(3), So HC(11), Davies RW(12), Patrice A(13), Dent R(14), Mangino M(15), Hysi PG(15), Dechaume A(16), Huyvaert M(16), Skinner J(17), Pigeyre M(18), Caiazzo R(18), Raverdy V(13), Vaillant E(16), Field S(19), Balkau B(20), Marre M(21), Visvikis-Siest S(22), Weill J(23), Poulain-Godefroy O(16), Jacobson P(24), Sjostrom L(24), Hammond CJ(15), Deloukas P(25), Sham PC(11), McPherson R(26), Lee J(27), Tai ES(28), Sladek R(29), Carlsson LM(24), Walley A(30), Eichler EE(31), Pattou F(18), Spector TD(32), Froguel P(33). Comment in Nat Rev Endocrinol. 2014 Jun;10(6):312. Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10(-14)) and serum enzyme levels (P < 2.20 × 10(-16)), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = -0.15 (0.02) kg/m(2); P = 6.93 × 10(-10)) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10(-10)). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies. PMID: 24686848 ------------------------- [4] Perry, G. H., Dominy, N. J., Claw, K. G., Lee, A. S., Fiegler, H., Redon, R., et al. (2007). Diet and the evolution of human amylase gene copy number variation. [10.1038/ng2123]. Nat Genet, 39(10), 1256-1260.
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