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It seems simple enough: if you eat only as many calories as you burn, you won’t pack on the pounds. Yet for many, balancing this equation is anything but easy. Obesity has become one of the most significant public health threats facing the United States and other developed countries. One-third of adults in the United States today can be considered clinically obese.
While lifestyle choices are certainly important, research has shown that genetics plays a significant role in determining a person’s propensity for being overweight or obese. One especially potent variant in the FTO gene has been consistently linked with weight in Europeans.
In a study of Scottish children published online yesterday by the <a href="http://content.nejm.org/cgi/content/short/359/24/2558" target="_blank" rel="noopener">New England Journal of Medicine</a>, researchers suggest that this FTO variant may contribute to obesity by leading kids to chose foods that, pound for pound, pack a more powerful calorie punch. 
Seventy-six kids between the ages of four and 10, selected from a larger study of 2,726 children who were having their height, weight, and FTO genotypes evaluated, also had their energy expenditure and food intake measured.
There was no difference in the number of calories burned while at rest between children who carried the higher weight-associated version of FTO and those who did not. Energy burned due to physical activity was actually higher for carriers than non-carriers. This suggests that the FTO variant isn’t affecting the basal metabolism rate or conferring a proclivity for a sedentary lifestyle.
There was also no difference in the total weight of the food ingested by the kids with the version of FTO linked to obesity. But these children did consume more calories than their non-carrier friends. The foods they chose during the test meals had “higher energy density” &#8212; they contained more calories per unit weight.
The authors note that most obesity disorders caused by defects in single genes (such as MCR4) affect eating behavior. These new results, and those of other studies (a few examples <a href="https://www.ncbi.nlm.nih.gov/pubmed/19053021?ordinalpos=1&amp;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" target="_blank" rel="noopener">here</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/18838977?ordinalpos=2&amp;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" target="_blank" rel="noopener">here</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/18583465?ordinalpos=3&amp;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" target="_blank" rel="noopener">here</a> and <a href="https://www.ncbi.nlm.nih.gov/pubmed/18842783?ordinalpos=4&amp;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" target="_blank" rel="noopener">here</a>), show that the common FTO variant is no different. It is unclear, however, whether FTO affects appetite regulation or the ability to sense how much food has been ingested.
In an accompanying <a href="http://content.nejm.org/cgi/content/full/359/24/2603" target="_blank" rel="noopener">editorial</a> in NEJM, Dr. Rudolph Leibel says that although the proportion of obesity in the general population that can be attributed to variation in the FTO gene region is high, it’s probably still not enough to start using this SNP as a clinical screening tool.
But he goes on to say that in the not-so distant future more variants such as this one will be found and physicians will be able to assess a “score” based on maybe 15 to 20 genes to predict an individual’s risk for obesity.
“The important role that environment plays in enabling or resisting such susceptibility is clear evidence that such risk can be modified,” Leibel concludes.

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Gene Variant Linked to Obesity Affects Food Choices in Children

<img loading="lazy" decoding="async" class="alignright size-full wp-image-1702" title="milkshake" src="https://blog-api.23andme.com/wp-content/uploads/2008/10/milkshake.jpg" alt="" width="284" height="423" srcset="https://blogcms.23andme.com/wp-content/uploads/2008/10/milkshake.jpg 284w, https://blogcms.23andme.com/wp-content/uploads/2008/10/milkshake-201x300.jpg 201w" sizes="auto, (max-width: 284px) 100vw, 284px" />
Although obesity was seen as a sign of social status during the Renaissance, it’s been known since <a href="http://classics.mit.edu/Hippocrates/aphorisms.2.ii.html" target="_blank" rel="noopener noreferrer">long before then</a> that being overweight is actually unhealthy.
We all know that carrying around extra pounds increases the risk for high blood pressure, diabetes and cardiovascular disease, yet one out of three Americans is obese.
New research, published online today in <a href="https://dx.doi.org/10.1126/science.1161550" target="_blank" rel="noopener noreferrer">Science</a>, suggests that for some obese people, genetic variations may desensitize the brain&#8217;s reward centers, making food less satisfying and leading to the consumption of more calories followed by the predictable result – weight gain.
<h6>Dopamine</h6>
When we eat, feelings of pleasure are produced by the release of a chemical called dopamine into the brain. Recent research has shown that the brains of obese people have fewer dopamine-responsive receptors; this deficit may decrease the pleasure obese people get from food and prompt them to overeat in order to compensate.
“Individual differences in how the brain processes food reward have been postulated to play a role in explaining why some, but not all, people are gaining weight in an environment where calories are plentiful. Our finding is exciting because it supports this possibility by demonstrating an association between an abnormal response to food and future weight gain — and it shows that this relationship depends on your genetic make-up,” said study author Dana Small in a statement.
<h6>The Study</h6>
Small and her colleagues examined 43 college women and 33 adolescent girls using functional magnetic resonance imaging scans, which analyze brain activation by measuring blood flow in the brain, while the study subjects tasted either a chocolate milkshake or a flavorless solution.
In both study groups, women with higher body mass indices (BMI) had lower levels of activation in dopamine-responsive areas of their brains as they tasted the milkshake. This relationship was significantly stronger in women with one or two copies of a variation in the dopamine receptor gene DRD2 that scientists call the “Taq1A A1 allele”.
The A1 allele has been associated with fewer dopamine receptors in the brain. Previous research has shown that people with one or two copies of the A1 allele are more likely to be obese. Other traits – such as alcoholism, obsessive-compulsive disorder, and error avoidance — have also been linked to the A1 allele and thus the brain’s reward pathways.
After one year, the researchers found, women with one or two copies of the A1 allele who had also shown lower brain activation in response to food gained more weight, possibly because of their diminished pleasure response.
“Identifying changes in behavior or pharmacological options could correct this reward deficit to prevent and treat obesity,” said the study’s lead author Eric Stice.

Genetics May Dull Pleasure Response to Food

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Obesity affects about one out of three adults in the United States. Because obese people are at increased risk of high blood pressure, diabetes, cardiovascular disease, and other health problems, many authorities consider it one of the most significant public health problems in the developed world.
Of course, diet and exercise are important parts of maintaining a healthy weight, but some people need a little more help. Sibutramine (marketed by Abbott Laboratories as Meridia ® in the U.S.) is a drug that creates a feeling of fullness, prevents the decline in metabolic rate usually associated with low-calorie diets and causes weight loss, especially when combined with behavioral therapy.
<h6>Genetics and Responsiveness to Treatment</h6>
But success with sibutramine is variable — for some people it just doesn’t work. New research, published in the October issue of <a href="http://www.gastrojournal.org/article/S0016-5085(08)01317-6/abstract" target="_blank" rel="noopener noreferrer">Gastroenterology</a>, shows that genetic differences might be to blame.
“Our results suggest the genetic make-up of patients could predispose their responsiveness to a drug. This could have important implications for the future of personalized molecular-based or individualized medicine,” said the study’s lead author Dr. Michael Camilleri in a statement.
Using a sample of 158 overweight and obese people, researchers at the Mayo Clinic tested the effectiveness of sibutramine therapy compared to placebo over 12 weeks. All participants also received behavioral therapy.
<h6>Study Results</h6>
The researchers found that weight and body mass index were significantly reduced in patients taking sibutramine compared to placebo, as was expected from previous research. But upon further inspection of the data, the researchers found that only people with certain versions of three different genes experienced significant weight loss.
People with a variant in the GNÎ²3 gene, had success with sibutramine, losing about 13 pounds. People with another variant in the Î±2A gene, lost even more weight — more than 17 pounds on average.
The third genetic marker scientists investigated, known in the scientific literature as 5-HTTLPR, is a stretch of DNA that comes in a long and short form. Only people with one or two copies of the short version of this marker had significant weight loss with sibutramine.
“Genetic variations may help select obese patients who are more likely to experience improved outcome with this treatment. Since the different markers were present in almost 50 percent of patients, the inclusion of screening for the genetic markers before prescribing the medication may even be cost-effective from a public health perspective,” Camilleri said.
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Genetic Variants Affect Weight Loss Drug Effectiveness

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The connection between <a href="http://www.cancer.gov/cancertopics/factsheet/risk/obesity" target="_blank" rel="noopener">obesity and cancer</a> is well established. As many as 25 to 30 percent of several major cancers — colon, breast (postmenopausal), endometrial, kidney, and esophagus — may be accounted for by obesity and physical inactivity. Some studies have also found links between obesity and cancers of the gallbladder, ovaries, and pancreas.
It is not yet clear to scientists, however, how obesity increases the risk for certain cancers. Part of the answer may lie in a hormone released by fat cells &#8212; adiponectin. Decreased blood levels of this hormone, which are found in obese people, have been <a href="https://www.ncbi.nlm.nih.gov/pubmed/18265479?ordinalpos=1&amp;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum" target="_blank" rel="noopener">linked</a> with breast, endometrial, prostate and colon cancer.
A new study published today in the <a href="http://jama.ama-assn.org/cgi/content/full/300/13/1523" target="_blank" rel="noopener">Journal of the American Medical Association</a> provides further evidence for adiponectin being the link between obesity and cancer. Researchers have demonstrated that a variant in the gene that encodes the hormone influences the risk of developing colorectal cancer.
Kaklamani et al examined several SNPs in the adiponectin and adiponectin receptor genes in a total of 629 people with colorectal cancer and 855 people without the disease. All subjects except for 37 cases and 37 controls were of European ancestry. The researchers found that people with one or two Gs at rs266729 in the adiponectin gene had 27% lower odds of developing colorectal cancer compared to those with two Cs.
(23andMe customers can look up their data for rs266729 using the Browse Raw Data feature)
According to the report’s senior author, Dr. Boris Pasche, these research findings could help identify people who would benefit from increased colorectal cancer screening.

“Our hope is that we can significantly improve the screening and early detection for this disease, and open new avenues for better understanding the genetic and lifestyle factors that influence colon cancer risk, “ he said in a statement.
Pasche went on to caution that additional studies are needed to confirm whether those without the adiponectin variant that appears to protect people from colorectal cancer will benefit from cancer-prevention lifestyle changes such as diet and exercise.
A different variant in the adiponectin gene was recently identified as a <a href="https://www.ncbi.nlm.nih.gov/pubmed/18451143?ordinalpos=1&amp;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum" target="_blank" rel="noopener">modifier of breast cancer</a> risk in a study co-authored by Pasche. Understanding how variants in this gene influence breast and colorectal cancer risk, and whether the variants affect the risk for other cancers, will require more research.
Colorectal cancer is the second-leading cancer killer of Americans. According to estimates from the American Cancer Society, 149,000 people will be diagnosed with the disease and 50,00 will die this year alone.

Genetic Link Between Obesity and Colorectal Cancer

<img loading="lazy" decoding="async" class="alignright alignnone size-medium wp-image-375" style="float: right;" title="bluescale" src="https://blog-api.23andme.com/wp-content/uploads/2008/07/bluescale-300x222.jpg" alt="" width="300" height="222" />European researchers have identified variations in the PCSK1 gene that could influence obesity risk in both adults and children. The <a href="https://dx.doi.org/10.1038/ng.1077" target="_blank" rel="noopener noreferrer">results</a>, published online in Nature Genetics, are based on data collected from nearly 14,000 people in five European countries.
The team was led by David Meyre and Philippe Froguel of the Pasteur Institute in France, who have been studying the genetics of diabetes and obesity.
The researchers were inspired by the <a href="https://www.ncbi.nlm.nih.gov/pubmed/9207799?ordinalpos=4&#038;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" target="_blank" rel="noopener noreferrer">earlier</a> research of British colleagues, who discovered a rare mutation in the <a href="http://obesitygene.pbrc.edu/cgi-bin/ace/gene/acedb?name=PCSK1" target="_blank" rel="noopener noreferrer">PCSK1</a> gene about a decade ago. That mutation causes obesity by preventing the production of an enzyme involved in metabolism. 
 
For this study, Meyre, Froguel and their colleagues started by examining genetic data from 1,045 obese and 1,265 non-obese French adults. They found six variants — or SNPs — in PCSK1 that showed a strong association with obesity. The researchers narrowed their list to just two SNPs that cause protein sequence changes: rs6232 and rs6234/rs6235. Because the latter two SNPs are linked, they were treated as one variation by the researchers. (23andMe customers should note that while our service does not currently offer information on rs6234 or rs6235, SNP rs10515237 can be used as a direct substitute for this variation.)
An association between obesity and the PCSK1 variants was also observed when the researchers sampled Danish adults, Swiss adults, French children and Swedish families. A sample of children from Germany found an association with SNP rs6232, but not rs6234/rs6235.
After compiling all their data, the researchers found that each copy of the riskier C version of rs6232 increased a person’s odds for obesity 1.34 times over the TT genotype. Each copy of the riskier G version of rs10515237 — which 23andMe uses instead of rs6234/rs6235 — increased odds for obesity 1.22 times over the AA genotype. 
In laboratory experiments, the researchers found that while the obesity-associated variants of PCSK1 found in this study do not interfere with production of the enzyme, rs6232 did reduce the enzymatic activity of the PCSK1 protein by 10%. Research in mice has shown that a change in the mouse PCSK1 gene very similar to the C version of rs6232 in humans <a href="http://hmg.oxfordjournals.org/cgi/content/abstract/15/11/1884" target="_blank" rel="noopener noreferrer">results</a> in increased fat accumulation and obesity.
In the following table, “Effect” is the increase in odds of developing obesity conferred by each copy of the riskier version of a SNP. SNPs where we are providing a proxy for the ones originally reported in the paper are marked with an asterisk. This information applies only to people with European ancestry.
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obesity — Page 2

Gene Variant Linked to Obesity Affects Food Choices in Children

Genetics May Dull Pleasure Response to Food

Genetic Variants Affect Weight Loss Drug Effectiveness

Genetic Link Between Obesity and Colorectal Cancer

Researchers Find Genetic Variants That May Influence the Risk For Obesity

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