Obese child with tray of food 500 x 375

A few weeks ago, an article in the New York Times by Gina Kolata laid the blame for the obesity epidemic afflicting us at our genes. Kolata reviewed work suggesting that genes are involved in obesity, with the implication that a fight to lose and maintain a lower weight is not only excruciating, but also practically futile.

That simply didn’t sound right. At least 10 genes have been discovered thus far that are involved in obesity and diabetes; more are bound to be discovered. We also know that the U.S. population is fast approaching the 50% mark of overweight (BMI 25-29.99) or obese (BMI >30). These genes presumably are not recent mutations. Why is it then, that only relatively recently did these genes express themselves to cause the outbreak of obesity? I think the answer is quite obvious: We have here a classic case of genetic/environmental interaction. The genes have been there all along; they haven’t changed. The new elements that caused such a massive upward shift in BMI are the invention of the car, television, computers—all leading to a sedentary lifestyle. Couple this with profound changes in our dietary and eating habits, resulting in a significant increase in caloric intake, and you’ve got an inescapable outcome: weight gain.


Don’t go shopping for food when you are hungry

I don’t know who first pronounced this maxim, but I am sure many of us rediscovered it many times, independently. What we actually discovered is that hunger is such a powerful physiological drive that no rational, moderating influence can keep it in check.


The hunger drive

Our gut reaction, so to speak, to hunger is primarily hormonal. Fat cells secrete a hormone, leptin (leptos means thin, in Greek), that travels to the brain and signals a message of satiety; the more leptin, the less hunger. Another hormone, called ghrelin, is secreted from the stomach when it is empty, and its signal to the brain is hunger; the more ghrelin, the more hunger. This description is obviously a vast oversimplification, but the basic mechanism is clear: Our sense of hunger or satiety is a balance between hormones with opposing influences on the center of the brain that controls feeding. This area, called the hypothalamus, has neuronal connections to two other important areas: the amygdala and the nucleus accumbens. Activation of the amygdala, when the hypothalamus senses hunger, causes a sense of alarm, sometimes accompanied by aggressiveness, easy irritability, and other hard-edged feelings. On the other hand, a sense of satiety and fullness activates the nucleus accumbens, which is the seat of all the warm and fuzzy feelings, like reward and pleasure. The neurotransmitter that mediates this sense of pleasure is dopamine.


The cocaine connection

It turns out that dopamine is also secreted in the nucleus accumbens in response to cocaine, amphetamines, and other recreational drugs. In fact, the response of the cells that carry the dopamine receptors to the sudden rise in dopamine concentration is to reduce the number of receptors, so as to keep the stimulus within manageable bounds, so to speak. This phenomenon is called receptor downregulation. To keep the pleasurable sensation at its previous level, one needs to take even more cocaine, which in turn causes even more downregulation. You can readily see the neurobiological downward spiral that we call addiction.

Lo and behold, the same pattern is seen in brain scans during binge eating: Surfeit of dopamine, activation of the nucleus accumbens, and downregulation of dopamine receptors.


The brain’s “adult supervision”

Of course, being civilized creatures, we could not let ourselves be governed by such “primitive” drives as pleasure and reward on the one hand or anxiety, aggression, and rage on the other. Indeed, evolution endowed us with a highly developed area in the brain called the prefrontal cortex. This is the seat of judgment and rational decision-making. It weighs the messages arriving from the reward and anxiety centers and renders judgments that find their expression in what we call behavior.

However, this Solomonic wisdom does not always prevail. When exceptionally strong messages arrive from one center, they overwhelm the messages from the other, and the judgment of the prefrontal cortex becomes skewed or completely overwhelmed by the flood of the incoming powerful signals. Each one of us, after a long period of fasting, must have felt an overwhelming desire to binge-eat. Only when we are finally disgustingly stuffed, do we ask ourselves: What am I doing? In neurobiological terms, the storm of signals from the amygdala (hunger to the point of anxiety) and the nucleus accumbens (“how sweet it is” and “the hell with the diet!”) subsided, and the ever stern, judgmental prefrontal cortex reasserts itself (“have you no shame?”).


So, is it genes or addiction?

I believe that the addiction model is a more plausible explanation of the overeating epidemic that is afflicting us now. It also explains the extreme difficulty in “kicking the habit”, losing weight, and maintaining it over a long period of time. As any recovered drug addict will tell you, one never really kicks the habit; it is a constant battle, and one is always on the brink.

The encouraging aspect of this grim picture is that addiction is susceptible to therapeutic intervention. There are drugs that can blunt the addictive urge. For instance, the drug naloxone reverses the effects of morphine. Interestingly, naloxone also blunts the hunger drive and reverses binge-eating.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.