Is There a Fat-o-Stat?

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Any system of physiological regulation requires a way for the body to sense the quantity of a specific substance present and to translate that information into actions that keep that variable within a desired range. The moment-to-moment energy needs of human cells, for example, are met by glucose, derived from food, circulating in the bloodstream. Normally the body keeps glucose levels within very tight limits. When blood glucose rises, specialized cells in the pancreas detect the change and secrete extra insulin, which triggers responses in muscle and adipose that cause those tissues to take in and utilize more glucose, while the liver responds by decreasing its own glucose production.

The adipose cells convert the excess energy they have taken in to triglyceride, a fatty acid. When food is not available and insulin levels fall, the fat cells release triglycerides back into the bloodstream, where they are transported to the liver and broken down into ketones, which can serve as fuel for muscle and the brain.

Studies of both animals and humans have long suggested that the mammalian body has mechanisms for monitoring the amount of energy it has stored as fat and for regulating that resource to remain near a particular level. If an animal has been at a stable weight, for example, significantly altering its energy intake will produce physical and behavioral changes that appear to be geared toward restoring weight to the previous level. An animal whose food is suddenly restricted tends to reduce its energy expenditure both by being less active and by slowing energy use in cells, thereby limiting weight loss. It also experiences increased hunger so that once the restriction ends, it will eat more than its prior norm until the earlier weight is attained. Likewise, after intentional overfeeding, an animal will start to expend more energy and exhibit reduced appetite, with both states persisting until weight falls to the previous level.

The consequences of having no regulatory system for controlling body weight would be substantial. Just a 1 percent excess of energy consumption over expenditure, for instance, could cause an average-size man to gain 60 pounds over 30 years. But do humans have an active system that maintains our stored energy balance, analogous to the mechanisms that control circulating glucose levels? The answer is yes. Though imperfect, such a system does exist and investigators, including our respective research groups, are making encouraging progress toward identifying its components.

As the pieces of this puzzle come together, a general observation can be made that may disappoint but will probably not surprise anyone who has struggled to lose weight: the human body's regulation mechanisms seem to be slightly biased in favor of preserving fat rather than eliminating it. In light of fat's value to survival, this tendency makes evolutionary sense. Over time, evolution could even have favored slight variations in relevant genes that produced the "thriftiest" management of precious energy stores.

Differences in obesity susceptibility among subgroups of people can also sometimes be tied to differing versions of particular genes. Very recently, for example, genome-wide scans performed on nearly 40,000 study subjects around the world identified a gene called FTO whose variation was linked to obesity. In every country studied, carriers of one version of the FTO gene were on average three kilograms heavier than others in their population and had nearly double the risk for becoming obese. At this point, the function of the FTO gene and how it might promote obesity are completely unknown, but its association with increased body weight suggests that it might have a role in weight regulation.

Genes do not function in a vacuum, however, and the genes of the human population in general have not changed over the past few decades. Explaining the relatively recent epidemic of obesity will therefore require a much better understanding of how variant genes interact with a person's environment to influence body weight as well. Some important environmental factors are obvious, such as the reduced need for physical exertion to survive and the increased quantity and quality of available food. Many other environmental variables are less self-evident and still poorly comprehended, such as the effect of nutrition during fetal development on body weight in later life. Stress, sleep deprivation and even viral infections and the composition of benign microbial communities within the body are additional factors that may affect an individual's fat regulation.

Identifying the genes that are normally involved in the body's management of fat is nonetheless allowing researchers to clarify some of the fundamental mechanisms at work. Not surprisingly, following the trail of protein signals encoded by those genes often leads to the master command center for many physiological processes, the brain.