Fat? Maybe you can't blame your genes after all

--"Fat? Blame your genes, say doctors" --"Overweight? Maybe you really can blame your genes" --"Blame your genes for obesity" Headlines such as these have become a staple of science and health journalism. Are they right? Are obese people really helpless victims of their genes? Let us begin by distinguishing between "monogenic" obesity and what scientists call "common" obesity. Monogenic obesity, as the name implies, is caused by a mutation in a single gene, which is inherited in a Mendelian fashion, just as conditions such as sickle-cell anemia and cystic fibrosis are. In the case of monogenic obesity, the mutation derails the body's ability to turn off hunger signals after an individual has eaten. This type of obesity usually is characterized by insatiable hunger and severe, early-childhood-onset obesity. Monogenic obesity in turn is divided into two subcategories: syndromic and non-syndromic.

Syndromic obesity is associated with specific genetic syndromes, which usually include mental retardation. The best known of these syndromes is Prader-Willi Syndrome, which is associated with low IQ, reduced muscle mass, and hyperphagia, or uncontrollable eating. Moreover, the reduced muscle mass of people with PWS means that their caloric requirements, per kilogram of body mass, are only about 60% of those of normal individuals. Notably, even individuals with PWS can have a normal weight if someone else controls their caloric intake; the fat does not magically appear on their bodies. Merlin Butler is a board-certified clinical geneticist and a Professor of Psychiatry and Pediatrics at the University of Kansas Medical Center. In a telephone interview he noted that some individuals with PWS have IQ's well within the normal range, and some have even gone to college, but due to their inability to control their appetites they never can never live independently. "You have to monitor them, supervise them 24 hours a day seven days a week," Dr. Butler said. Unless someone else restricts their food intake, "they'll eat until the food is gone, or their stomach ruptures, or they fall asleep," Dr. Butler noted that injections of growth hormone can help people with PWS, increasing their lean body mass and enabling them to burn more calories and therefore sustain a food intake closer to that of a non-PWS person. However, at present there is no treatment for the hyperphagia. Luckily, these syndromes are rare: Prader-Willi Syndrome occurs in fewer than one out of every 10,000 births, and the other syndromes are even rarer. Non-syndromic monogenic obesity is caused by mutations in genes involved what is known as the leptin-melanocortin pathway. Leptin is a hormone produced by the adipose tissue which binds to receptors in the hypothalamus, the body's control center. The binding of leptin sets off a cascade of events which includes the release of melanocortin and other hormones which inhibit food intake and regulate energy expenditure.

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Stephen O'Rahilly is a Professor of Clinical Biochemistry and Medicine at the University of Cambridge. In a 1999 NEJM paper, he and his colleagues reported that administration of genetically engineered leptin results in dramatic weight loss in individuals whose obesity results from a deficiency of that hormone. In a telephone interview, Dr. O'Rahilly stated that individuals unlucky enough to have been born with two copies of the defective gene for leptin usually are the products of consanguineous unions, and usually in families living in poverty. He explained that these unfortunate individuals never feel satisfied, and he described heartbreaking scenarios in which their families bring themselves to the point of destitution, even starving their other children, in an attempt to satisfy the literally insatiable appetites of the child born with a deficiency of leptin. At least ten genes have been identified as playing a role in the leptin-melanocortin pathway. While mutations in the gene for leptin can be treated with injections of that hormone, there currently are no medical treatments for individuals born with defective versions of any of the other genes in the pathway, although scientists are working on it. Again, luckily, these conditions are extremely rare, and these genes usually have been located in consanguineous families. Dr. O'Rahilly estimates that, all told, defects in the leptin-melanocortin pathway account for something like 10-12% of cases of severe, early-childhood-onset obesity. The overwhelming majority of obese subjects (including people with PWS) have normal or elevated levels of this hormone, and shots of leptin do nothing to help them. The vast majority of obese subjects have what is called "common" obesity, (also known as polygenic obesity or exogenous obesity) meaning it is not inherited in a Mendelian fashion. The 11 May 2007 issue of Science announced the discovery of the so-called fat mass and obesity-associated gene, or the FTO gene. Dozens of other genes associated with increased body mass index, or BMI, have since been found. An impressive array of brainpower, not to mention money, has been thrown at this problem. The aforementioned Science paper lists 41 authors from 19 different institutions, along with the entire Wellcome Trust Case Control Consortium. The authors measured the BMI and examined the genomes of over 29,000 adults and children. And just what have we gotten in return for this outlay of time and effort?

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"We have to eat less"

The FTO gene comes in two forms, or alleles. The more common form is called the major allele and the less common form is called the minor allele. Individuals with two copies of the minor allele weigh more, on average, than those with two copies of the major allele. (As you might expect, individuals with one copy of each allele are somewhere in the middle.) How much more do they weigh? For an individual of average height, the difference is about eight pounds. All the other genes that have been linked to common obesity are correlated with even tinier differences in weight -- some as small as two ounces. Any such genes remaining to be discovered probably have even tinier effects. Giles Yeo is the Director of Genomics/Transcriptomics in the Department of Clinical Biochemistry at the University of Cambridge. In a telephone interview he explained that the FTO gene was the first gene for common obesity to be discovered precisely because it has the largest effect. He couldn't rule out the possibility that there were other genetic variants for common obesity with larger effects, but he said if they exist they must be rare. Even these tiny effects diminish or even disappear with exercise. A 2008 study of Old Order Amish individuals found that the FTO gene had no effect on body mass for those in the top half of the physical activity distribution. A Danish study published that same year likewise found that the FTO gene had no effect on body mass for those in the most physically active category; another study of Danish women published three years later found the same results. That same year, a study of US women found that, for those in the least active category, possession of two copies of the BMI-increasing FTO allele was correlated with an increase of 0.73 BMI units; for a women of average height, that translates to a little over four extra pounds. For the most active women, this difference shrunk to less than two pounds. Finally, a 2013 study published in PLoS Genetics looked at the interaction between exercise and genetic risk score, which is a function of the number of so-called "obesity genes" an individual is carrying. When the bottom 20% of the physical activity distribution was dropped from the analysis, the difference in weight between those with high and low risk scores was less than a pound. Should anyone be surprised? Our Paleolithic ancestors trekked for miles in search of the right kind of wood for making spears and they used those spears to take down wild horses and fend off saber-toothed cats from their kills, they banged out stone tools and used those tools to butcher the carcasses of their prey, and then they shouldered the meat and carried it home. All these activities took enormous amounts of energy. Our bodies evolved to be used. One study estimated that in order to match the total energy expenditure of modern-day hunter gatherers, we would have to walk 12 miles a day. Admittedly, most people would find this recommendation impractical to implement So how much exercise do we really need? One clue comes from the National Weight Control Registry, a project which tracks individuals who have provided documented evidence of major, long-term weight loss. The average member has lost 66 pounds and kept it off for more than five years. 90% of the members report that they exercise for at least an hour a day. (They also report that they eat less.) These findings were substantiated by a 2010 study published in JAMA which tracked 34,079 healthy US women for the period 1992-2007. The only women who did not gain weight in the course of the study were those who averaged the equivalent of an hour or more of moderate-intensity activity every day. Fortunately, it's not an all-or-nothing kind of deal. Just as the harms of obesity are dose-dependent, so are the benefits of exercise. A lot is better than a little, and a little is better than none at all. Unfortunately, as a society we seem to be going in the wrong direction on this one. A study published in August 2014 in the American Journal of Medicine found that for the period 1988-2010, the proportion of Americans who took no leisure-time exercise at all rose from 19.1% to 51.7% for women, and from 11.4% to 43.5% for men. During the same period, average BMI and the rate of abdominal obesity also rose substantially. Interestingly, the authors found no evidence that average caloric intake rose during this period. Every one of the experts interviewed for this article stressed the importance of exercise. Dr. Butler noted "Obesity is driven in our society by the environment: by the inexpensive excess food sources that we have that are calorically dense, and the decrease in physical activity." Dr. Yeo declared "Any type of exercise will improve your health. You should get any exercise you can, even if you can't get the 12 miles per day, which most of us can't. In lieu of that, we have to eat less or eat healthier. It's going to have to be one of the two if we're going to maintain our body weight and not gain." Dr. O'Rahilly summed up matters thusly: "There is no such thing as genetic obesity. There is a genetic predisposition to obesity, which can be nullified by exercise." List of Sources

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