Ghrelin and the Omnipresence of Food

It really is difficult to travel a mile in this country without being exposed to something trying to entice you to eat. Billboards, mini-marts, and restaurants have saturated our environment with visual cues that remind us of the importance of feeding. When at home the television, radio, or internet can be helpful if one has a tendency to forget the necessity of food—especially that of the fried, dripping, or cheesy variety. The advertisers behind all of these reminders are hoping that when you encounter them, your stomach will be coincidentally flooding your hypothalamus with ghrelin.

Ghrelin is a hormone produced by the gut. You may have heard of ghrelin’s counterpart: leptin, a hormone that is integral in letting the brain know you have had enough to eat. This is important, as can be seen by looking at mice with a genetic mutation that results in an inability to produce leptin:

Obese mouse

Ghrelin seems to play the role opposite to leptin’s, it lets you know that the stomach is getting empty and it is time to eat. Ghrelin levels are highest before a meal and lowest afterwards. When ghrelin levels are raised experimentally, people are found to eat more than those administered a placebo.

Ghrelin receptors (and leptin receptors) are especially prevalent in the hypothalamus, but a recent neuroimaging experiment shows that ghrelin may have a much more widespread effect on the brain.

A study published this week in Cell Metabolism describes the use of functional magnetic resonance imaging (fMRI) to investigate ghrelin-related brain activation. Participants were scanned while looking at food and nonfood images. Some of the subjects received an infusion of ghrelin before the fMRI.

The ghrelin injection resulted in an increase in brain activation in areas associated with evaluating the hedonic value of a stimulus—the “reward centers” of the brain, along with a large network that includes visual and memory areas. These are some of the same regions thought to be responsible for drug-seeking and other types of addictive behavior.

Thus, high levels of ghrelin may make our advertisement-laden and food-available environment a dangerous one in which to live. But the hormone may also represent a plausible method for treating obesity. Vaccines that raise an immune response against ghrelin have been shown to be effective in reducing weight gain in rats. Their use with humans is currently being investigated.

Until (and if) they are found to be effective it is best just to try to ignore the constant urgings all around us to “eat, eat, eat”.

Every Sweet Hath its Sour

People, along with many other animals, have a preference for sweet foods. This is putting it mildly, as our love of sugary sustenance has immensely influenced our culture, economy, and health. Even our vocabulary has been affected by an affinity for sugar, as the word “sweet” itself has a positive connotation, in English and other languages (e.g. la dolce vita).

But, our predilection for sweetness has come with a cost, as evidenced by a worldwide prevalence of obesity that is over 300 million. Obesity is not, as is sometimes implied, a condition that suddenly appeared within the last fifty years. The rate of obesity is, however, growing at an alarming pace, and has been for several decades. This has led to a similar increase in obesity-related illnesses, like type 2 diabetes, hypertension, and heart disease.

Why would evolution have left us with a preference for sweet foods, when it is these very same foods that make us fat and unhealthy? Part of the answer may lie in the fact that the environment in which our evolutionary ancestors lived didn’t have 64 oz. fountain sodas, frosting-covered donuts, and candy aisles. In their hunter-gatherer societies, food was much more scarce, so while we spend our days counting calories, they spent theirs searching for them. Sweet-tasting foods are usually an indication of high caloric content. They are also generally not poisonous, making them doubly valuable to a primitive food gatherer. So, a predilection for them would have been adaptive at one time, and may be an evolved mechanism. This hypothesis is reinforced by a widespread partiality for sweetness throughout much of nature.

A group of researchers from Duke University Medical Center have conducted a study, however, that calls into question the idea that a penchant for high-sugar foods is based on the ability to taste their sweetness. The group genetically engineered a line of mice that lack the ability to taste sweetness. They then exposed the mice to sugar water and water containing sucralose, a noncaloric sweetener. The “sweet-blind” mice demonstrated a preference for the actual sugar water. The preference appeared to be based not on sweetness, but calorie content.

This still fits in with the idea that the proclivity for high-calorie foods is an adaptive trait, but without the ability to taste sweetness as an indicator of the water’s calorie content, how did the mice know which water to drink? The researchers examined the brains of the mice and found that their reward system was activated by the caloric level of the water—independent of taste. The high-calorie sugar water raised dopamine levels and stimulated neurons in the nucleus accumbens, an area of the brain thought to be integral in reinforcing the value of rewarding experiences.

This activation of the reward system is one that seems to be separate from the hedonic aspect of pleasure. The affinity of the sweet-blind mice for high calorie water may represent the involvement of metabolic awareness in the reward system. This implies the brain’s understanding of "reward" is at a much deeper biological level than that which we normally associate with the word. It also is further indication of a separation between the hedonic and reinforcing aspects of the reward system (see the previous post on dopamine).

This finding could have real-world implications in helping to battle the obesity epidemic. If high-calorie foods are rewarding in and of themselves, it may help to explain our nation’s addiction to items that contain calorically fulsome additives, like high-fructose corn syrup. Reducing the prevalence of such additives could decrease the rewarding value of the food they are in, and thus reduce consumption.

It’s imperative that something is done soon to curb the rising rates of obesity. Our propensity toward heftiness may be partly due to a once evolutionarily adaptive trait that has become maladaptive in our modern environment. Thus, our difficulty in making the adjustment illustrates the power of genetics and evolution. But it should also remind us that evolution might be having a powerful effect right now. If so, it is being aided by fast food, mini-marts, and billions of dollars of advertising, and a society that may be too complacent to pay attention to the ramifications.

Thinking Thin Not So Easy

Our overweight population is arguable the most dangerous health crisis the United States is facing right now, and much of the rest of the developed world is heading down the same path. About 65% of the U.S. population is overweight, and over 30% are obese. Public awareness of this is rising slowly, resulting in half-hearted attempts by fast-food restaurants to add healthy items to their menus and in the proliferation of a diet industry that in many cases probably does as much harm as good. Needless to say, the trend seems to be continuing in the wrong direction. As we grow fatter as a nation, we also find diabetes, heart disease, and some types of cancer rising at alarming rates.

Many of the proposed solutions to this dilemma focus on public awareness and corporate responsibility, both of which are good things. Many scientists, however, are interested in finding the roots of the problem. There is a reason why human beings are inclined to eat fatty foods, and why the digestion of excess amounts of such foods results in the deposit of adipose tissue throughout the body. Think about this from an evolutionary standpoint. In an environment like that which our hunting and gathering ancestors lived, there were periods of food availability followed by days (or longer) where food was scarce. In this ancient world, the ability to store fat as adipose tissue would become adaptive, and the desire for fatty foods would have been beneficial as those types of food would result in stored energy that could sustain one over periods of scarcity. Today’s environment differs, however, in that food is available all the time, and those foods that are often the fattiest are those that require the least effort and money to obtain. Perhaps those behavioral remnants of our evolutionary past combine with the modern ubiquitousness of food to create the obesity epidemic we are witness to today.

But this obviously isn’t the whole story, for it doesn’t explain the difference between the 35% of the population who isn’t overweight and the 65% who are. Scientists hope that finding the reason for this disparity may lead to better methods to curb obesity and avoid the national health crisis we seem to be headed toward. There has been a great deal of research that supports a strong genetic influence in obesity. The number of genes involved, their interdependence, and the molecular mechanism of their influence, however, are yet to be determined.

Naturally some of research in this area is focused on the neural mechanisms that contribute to overeating. As eating is a rewarding process, much attention has been paid to dopamine abnormalities leading to obesity (for more discussion of dopamine and rewarding processes see last week’s post “Drugs, Love, & War: All the Same to the Brain?”). A recent discovery by William Bendena and Ian Chin-Sang of Queen’s University, however, has shown perhaps the most direct connection between neurotransmitter activity and overeating to date. Experimenting with worms that have distinct neurotransmitter similarities to humans, Bendana and Chin-Sang found a nervous system receptor that, when damaged, caused no change in the worms—until they were placed on food. Then they suddenly become lethargic, would not move away from the food, and gained fat at a much quicker rate than controls. When they added extra copies of the receptor to other worms, they became much more active, traveling great distances from their food supply. Of course much work must be done to apply these findings to humans, but it does suggest that perhaps there is a neurobiological mechanism that leads directly to lethargy and overeating. If so, it may be amenable to correction through pharmacological methods, which might be more successful than simply adding more salads to a fast food menu.