The center in the brain that regulates our food intake through sensations of hunger and satiety (the sense of fullness) receives a constant stream of signals through hormones, peptides, and proteins called cytokines. These proteins serve as signals for cell-to-cell communication.

There are a large number of signals, some are positive (they increase hunger) and some are negative (they make you feel full). The number of signals that are described increases almost every time I open a scientific journal. But the complexity isn’t only because there are a large number of signals. It is also because the responses to these signals can vary over a continuum from negative to neutral to positive to super positive. It all depends on which signals arrive at the hypothalamus (an area deep in the brain that controls many of our most basic functions, such as appetite, sex drive, and so forth) at any given time and any given physiological state. For instance, when you are wide awake, your brain responds to the stomach hormone, grehlin, with an urge to raid the refrigerator. However, your brain may be completely unaware of ghrelin’s signal when you are in a deep sleep.

To complicate matters even more, grehlin’s effect may be moderated by the influence of another hormone, leptin. Leptin is considered to be a “you are fat” signal. But it only works well in people who aren’t fat. Brains of obese people do not “hear” the leptin signal in the same way. These variations in hormonal response are only the tip of the iceberg when it comes to understanding the brain’s control over appetite and food-seeking behaviors.

When you think about the number of permutations theoretically possible, you realize that control of appetite and, thus, body weight, is a multidimensional jigsaw puzzle. Knowing this, makes it easier to understand why to date there is no single “magic pill” that significantly helps you control your weight over a long period of time. An even more frustrating fact is that, even if a drug shows effectiveness in controlling weight initially, most of the time the effect wanes and disappears completely within months. This is because no weight control signal acts on the brain in isolation. There are many signals that that act in concert on the brain. And they are working to make sure you maintain the status quo with respect to your body’s energy stores (a.k.a. fat).

Most diet pills available today target a single signal or alter the signal’s effectiveness by affecting its cell surface receptor. Why is that? It’s a good question (professors always say that when they don’t have a good answer). But some generalities may help us understand this phenomenon.

The first part of the answer has to do with the natural selection (no Kansas, there is no Intelligent Design to be found here, nor anywhere else in nature). We evolved as a species (Homo sapiens) about 300,000 years ago, give or take a few thousand years. All this time, except the last approximately 100 years, we were constantly involved in a struggle to avoid hunger.

Only about 10,000 years ago did we learn to domesticate plants and animals to cultivate them—the dawn of agriculture. Still, although food became more abundant, it was barely enough to provide a healthy diet to most of humanity. The problem humans faced was not obesity. It was undernourishment and the constant threat of famine.

In the last one hundred years or so, with the advent of farm machinery, fertilizers, and pesticides, our food supply has exploded and became more affordable. During this same time period, the automobile was invented and became a common mode of transportation. Translation: more food, less exercise.

It is then not surprising that natural selection, working along time spans of hundreds of thousands of years, strongly favored a system in which the hunger signals are powerful and the modulating and moderating signal are quite a bit weaker. This ensured that we never get complacent and were always on the prowl for something to eat.

The second part of the answer is somewhat related to the first. Biological systems have a variety of ways to adapt when there is a change in physiological circumstances. For instance, suppose we thought the following: If leptin signals to brain “fatness”, then why not provide a lot of such a signal in the form of a leptin diet pill? Indeed, experiments in mice and rats supported this concept. So, clinical trial in humans was initiated amid great hoopla in the media. But the human experiment was a flop—and no wonder.

If you think about it, nature has already done this experiment for us. Obese people secrete a lot of leptin, because it is produced in the adipose (a fancy word for fat) tissue, and obese people have an inordinate amount of that. So why are they still obese? And why are they ravenously hungry? Because the system adapted to the chronically elevated stimulation of leptin and simply “dialed down” its response.

Finally, you might ask how come mice and rats responded nicely to leptin and lost weight? Good question; we don’t really know. We have pat answers like, “mice are not human”, or “their physiology/endocrinology/biochemistry/genetics (your pick) is different.” But how different? We don’t really know.

Biology frustratingly complex? This is why I find it so fascinating.