Obesity Is in the Genes – Scientific American

In a recent monologue, the comedian James Corden addressed his struggles with being overweight. Despite his best efforts, he said, he has never been able to control his weight confessing that he has good days and bad months. The monologue was a response to an on-air editorial by Bill Maher, who argued that fat shaming needs to make a comeback, excoriating the obese for their lack of self-control. Which of them was correct? Are the obese to blame for their condition?

No. Recent research has revealed that obesity is to a very large extent encoded in our genes. Indeed, studies of identical twins reveal that the heritability of obesity ranges between 7080 percent, a level that is exceeded only by height and is greater than for many conditions that people accept as having a genetic basis. While there has also been an overall increase in the prevalence of obesity over the last several decades, it is the particular set of weight-regulating genes that a person inherits that determines who is lean and who is obese in 2019 America.

Could it be then, as Maher implies, that thin people control their urge to eat and the obese do not? For those who believe that being thin is a result of greater self-control, consider the case of a massively obese four-year-old boy in England, who weighed 80 pounds. After consuming a single test meal of 1,125 calories (half the daily intake of an average adult), he asked for more. This boy had a similarly affected eight-year-old cousin who weighed more than 200 pounds. Both children carry a genetic defect causing their obesity that runs in the family. The defective gene encodes the adipocyte hormone leptin, and the children do not produce it.

However, when they receive leptin injections, their appetite is reduced to normal, and they lose enormous amounts of weight. The boy in fact is now quite thin. These findings confirm that biologic factors play the key role in determining ones appetite undercutting the common misconception that food intake is primarily under voluntary control.

In normal people without leptin mutations, the hormone is secreted by fat cells into the bloodstream and then acts on specialized brain cells that regulate appetite. When the amount of fat increases, leptin production increases, and food intake goes down. When weight is lost, leptin decreases, which then stimulates appetite. This physiologic system acts in a manner analogous to a thermostat (or lipostat) that maintains body weight within a relatively narrow range.

This system serves a vital evolutionary function by maintaining optimal levels of adipose tissue, thus providing a source of calories when food is not available, a not uncommon occurrence during human evolution. However, the decreased mobility associated with excess fat can increase the risk posed by predators. The leptin system appears to have evolved to balance the risk of being too thin (starvation) and the risk of being too obese (predation). Indeed, the weight of all mammals is precisely regulatednotwithstanding that only humans have ever expressed a conscious desire to lose weight.

Specific genetic differences that predispose to obesity or leanness are then propagated by natural selection depending on whether starvation or predation was the greater risk. The weight of each individual is then stably maintained by the leptin system with remarkable precision. The average person takes in a million or more calories per year, maintaining weight within a narrow range over the course of decades. The body balances calorie consumption with expenditure, and with accuracy greater than 99.5 percenta precision far greater even than that on labels showing the calorie content of the food we eat.

Mutations in hormones are rare and there are only a few dozen patients who fail to produce leptin. So, while studies of these individuals establish a role for leptin to control appetite in human, defects in the gene itself are a very infrequent cause of obesity. However, mutations in the neural circuit that is regulated by leptin are more common, including mutations in the receptor for leptin. Patients with mutations cannot receive leptins signal and so also become massively obese. But because these patients cannot receive leptins signal, treatment with the hormone is ineffective and these patients are referred to as being leptin resistant.

The leptin receptor is expressed in the hypothalamus, a primitive part of the brain that regulates most basic biologic drives, including the basic drive to eat. In the hypothalamus, there are specialized neurons expressing the leptin receptor that regulate appetite. One type promotes food intake; a second neural population reduces food intake. Leptin acts by inhibiting the one and activating the other. Similar to mutations in the leptin receptor, mutations in other key genes downstream of the hypothalamus also cause human obesity. Recent genetic studies have shown that as many as 10 percent of markedly obese children carry mutations in one or another of these individual genes. Thus, when Maher categorically asserts that obesity isnt a birth defect, he is (mostly) wrong.

Another mistake that Maher and others make is to assume that the drive to eat is the same for all. Leptin regulates the intensity of the feeding drive. In its absence, patients report being unable to control their appetite and eat voraciously. One patient described it as hunger without end, akin to the hungriest youve ever been. That is how leptin deficient people feel all the time. This sensation appears to be similar for obese patients who lose weight (e.g., The Biggest Loser), the majority of whom put the weight back on

In aggregate, the genes that control food intake and metabolism act to keep weight in a stable range by creating a biological force that resists weight change in either direction. Moreover, the greater the amount of weight that is lost, the greater the sense of hunger that develops. So, when the obese lose large amounts of weight by conscious effort, their bodies fight back with a vengeance. If you think it is difficult to lose15 pounds, imagine what it must feel like to lose 50 or 100!

Can willpower restrain this drive over the long term? The evidence says that for the vast majority of people the answer is no. Yes, a relatively small proportion of patients do maintain long term weight loss. But willpower is not metaphysical, it is encoded in our cerebral cortex, where conscious thought resides. How the cortex successfully communicates with the hypothalamus varies among individuals. The precise ways that this communication happens is not yet known but is an area of active investigation.

What we do know tells us that if you are thin, you should thank your "lean" genes and refrain from stigmatizing the obese. A broad acceptance of the biologic basis of obesity would not only be fair but would allow us to collectively focus on health. Even modest amounts of weight loss, far less than would satisfy Maher, can improve health and this should be the objective for obese people who suffer from its medical complications.

While research is moving toward developing effective therapies for obesity, we are not there yet. In the meantime, we must change our attitudes and turn our focus from appearance and to improved health. The obese are fighting against their biology. But they also are fighting against a society that wrongly believes that being fat is a shameful, personal failing.

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Obesity Is in the Genes - Scientific American