In this post, I'll explain my current understanding of the factors that promote obesity in humans.
To a large degree, obesity is a heritable condition. Various studies indicate that roughly two-thirds of the differences in body fatness between individuals is explained by heredity*, although estimates vary greatly (1). However, we also know that obesity is not genetically determined, because in the US, the obesity rate has more than doubled in the last 30 years, consistent with what has happened to many other cultures (2). How do we reconcile these two facts? By understanding that genetic variability determines the degree of susceptibility to obesity-promoting factors. In other words, in a natural environment with a natural diet, nearly everyone would be relatively lean, but when obesity-promoting factors are introduced, genetic makeup determines how resistant each person will be to fat gain. As with the diseases of civilization, obesity is caused by a mismatch between our genetic heritage and our current environment. This idea received experimental support from an interesting recent study (3).
Researchers have identified a number of genetic factors that influence obesity risk in industrial nations (an obesity-promoting environment). These tend to be linked to genes most highly expressed in the brain, and particularly in the region known as the hypothalamus, which is central to the regulation of body fatness (4, 5). In addition, they have found gene variants in the dopamine signaling pathway that associate not only with obesity, but also with susceptibility to drug and gambling addiction-- these genes influence reward sensitivity (6, 7, 8, 9, 10). A plausible idea is that genetics influences 1) how well each person's hypothalamus resists the factors that promote obesity in the 21st century, and 2) how susceptible each person's reward centers are to hyperpalatable/hyper-rewarding food.
This is why statements like "I eat junk food, and I'm not fat, therefore junk food doesn't cause obesity" aren't very convincing. Due to individual variability, these anecdotes are not always useful for understanding population-level changes. Two different people can be exposed to the exact same food environment, but genetic differences will encourage leanness in one and obesity in the other. This is part of the reason why I don't see obesity as a "moral failure".
According to USDA data, Americans today eat an astonishing 425 more calories per day than they did in 1970** (11). That is the reason for the obesity epidemic, plain and simple. However, that fact doesn't tell us why we're eating more calories, so its usefulness is limited.
The increase in calorie intake has come primarily from refined carbohydrate, but even that doesn't get us very far, because why did we decide to eat more refined carbohydrate? Probably because of the systematic efforts of commercial food manufacturers to increase the palatability/reward value and availability of processed food. In the last four decades, the US has become saturated with hyperpalatable/rewarding commercial and restaurant foods including fast food, soda, french fries, chips, candy and other industrial products. I've seen people claim that they ate these things just as much in the 1960s and 70s, but the USDA and National Restaurant Association data show otherwise (12). The qualitative changes in the US diet have been swift and profound-- I'll be reviewing that evidence in future posts.
There is a lot of research suggesting that food reward/palatability is an important factor in body fatness (13, 14, 15), but it isn't the only factor. I regret calling food reward "a dominant factor" in my food reward series, because that phrase has been widely misinterpreted as indicating that I think food reward is the only factor in obesity. Finding examples of people, or even whole cultures, that the theory doesn't explain, invalidates the hypothesis that food reward accounts for 100 percent of obesity. Of course, that's not the hypothesis that I, or other obesity researchers, favor. I'm sure there are exceptions in which food reward/palatability doesn't explain obesity, although I haven't found a whole population yet that is a clear exception, in the sense that major changes in palatability/reward do not correlate with changes in body fatness. Food reward/palatability is the single most compelling explanation I've come across for the US obesity epidemic so far, but it does not exclude other factors.
Another factor that contributes to obesity is inactivity. The human body is designed to engage in physical activity, and if that doesn't happen, we don't function optimally. Exercise maintains leptin sensitivity in the hypothalamus, and the rodent literature suggests that without it, leptin sensitivity declines and fat mass increases (16, 17). This offers an explanation for why overweight people don't necessarily compensate for the calories they burn while exercising by eating more (18). If energy expenditure is increased, but leptin sensitivity is increased, the balance between these two factors will determine hunger and food intake. Calorie compensation is highly individual, and accounts for the variability in the ability of exercise to cause fat loss between people (19). Treadmill-type exercise isn't a very effective way of reversing obesity for most people, however it can increase the effectiveness of dietary interventions, and it may work better for preventing obesity than for reversing it (20, 21). It's also good for general health, up to a point.
There are probably other factors involved as well. Animal experiments have taught us that inflammatory signaling in the hypothalamus can cause leptin resistance and increase body fatness (22, 23). Anything that increases inflammatory tone in the brain is a potential contributor. The potential causes are murky, but may involve altered gut flora, insufficient dietary fiber, insufficient polyphenols, poor omega-6:3 balance, psychological stress, insufficient sleep, micronutrient deficiency, and physical inactivity. Fiber and exercise are the most solid, because they have been shown to protect against fat gain in rodents and humans (24, 25, 26, 27, 28). The rest are just possibilities, according to my current knowledge-- nothing to hang your hat on.
There's an additional factor that I've come to believe may be an "elephant in the room" when it comes to insulin/leptin resistance and chronic inflammation, and that is, ironically, energy excess. Glucose and fatty acids, the body's main two fuels, are toxic when present in the bloodstream in excess. When someone eats too many calories, his body has to deal with the excess. The healthiest way of doing this is actually to shunt the excess energy into fat tissue where it is inert. If the fat tissue does not have a sufficient affinity for the excess fat, free fatty acid levels in the circulation may rise, and tissues and cells may accumulate fat and fat metabolites (e.g., triglycerides, diacylglycerides, ceramides and fatty acyl CoAs). This is what we see in people who have a disorder of fat tissue called lipodystrophy-- since their fat tissue can't absorb much fat, they accumulate fat where it isn't supposed to be and develop profound insulin resistance (29). This is presumably because of the insulin resistance-promoting and inflammatory effects of some of these fat metabolites (30, 31).
Even in people whose fat tissue does have a high affinity for the excess circulating fat, which is most common at least initially, if fat mass increases enough, fat cells become insulin resistant, release more fatty acids into the circulation and fail to clear fatty acids from the circulation after a mixed meal (32, 33, 34). Essentially, fat tissue loses its formerly high affinity for excess fat, and these undesirable fat metabolites accumulate in lean tissues in a manner reminiscent of lipodystrophy. This contributes to insulin resistance and glucose intolerance by the same mechanism described above, creating an excess of circulating glucose as well, which together with the excess of fatty acids can enhance chronic inflammation, further insulin resistance and damage the insulin-secreting pancreas.
Consistent with this idea, diet-induced obesity in rats is accompanied by the abnormal accumulation of lipids in the hypothalamus*** (35). This has been shown to inhibit leptin and insulin signaling in the hypothalamus via a protein called PKC theta, which is similar to how fatty acid accumulation in the periphery is thought to inhibit insulin signaling (36, 37, 37B). Suppressing PKC theta activation in the hypothalamus attenuates diet-induced obesity in rats (38).
Therefore, it's possible that an excess of circulating fatty acids (and perhaps glucose) itself acts to raise the setpoint through the gradual accumulation of fatty acid metabolites and inflammation in the hypothalamus, promoting leptin resistance and creating a "cascading failure" of energy balance regulation, glucose metabolism and inflammatory signaling. This would explain why people in affluent societies have trouble staying lean as they age, as well as why obesity is so difficult to treat. I think this is likely to be a late stage process, occurring after significant body fat accumulation and essentially "cementing" the increase in body fatness. The early stage that causes the initial rise in body fatness probably has more to do with food reward/palatability/availability, although that should remain a factor even after obesity is well established.
Putting it All Together
The basic idea is that in genetically susceptible people, excessive food reward/palatability/availability and inactivity cause overconsumption and an increase in the body fat setpoint, followed by the eventual accumulation of fat metabolites and inflammation in the hypothalamus, which exacerbate the problem and make it more difficult to treat. Other factors, such as micronutrients, gut flora, fiber, fat quality, polyphenols, sleep and stress, may also play a role. I think this is a reasonable working hypothesis of why obesity has increased so rapidly in the last 30 years, and is so difficult to treat once established. I believe these ideas are broadly consistent with the research and opinions of senior obesity researchers I respect.
* More precisely, these studies measure the heritable component of body mass index variation.
** Estimates I've seen range from 250 (NHANES) to 570 kcal/d (39), but everyone agrees there's been a large increase.
*** Palmitoyl and stearoyl CoA specifically. These are lipid metabolites on their way to being burned by the mitochondria. If the cellular influx of lipid exceeds what the mitochondria can burn, fatty acyl CoA and other lipid intermediates accumulate.