We have made great strides in understanding the root causes of the obesity epidemic that is sweeping the whole world. Basically, our metabolism is geared to horde calories and it makes perfect sense. And not just for us humans.

Our evolutionary cousins the apes, and our common ancestors the monkeys faced the same dilemma. That is, how do you survive in an environment where food supply is not assured from one day to the other, particularly when most of it is of low caloric density? The answer is that you conserve, you save for a rainy day (lessons that we seem to forget nowadays, but I digress). Indeed, the metabolically-prudent individuals who were equipped with a set of hormones that favor calorie storage had a selective advantage over the metabolically- profligate individuals whose metabolism adhered to the siren song of “eat and drink, for tomorrow we die”.

John Maynard Keynes, a legendary British economist and investor answered one of his critics who had accused him of changing his mind: “When
circumstances change, I change. What do you do, sir?” This pithy riposte encapsulates our metabolic  conundrum: circumstances changed, and radically so; we don’t have to run miles every day to find some food, and the caloric density of our diet has increased precipitously. But we didn’t adjust; evolution cannot change rapidly enough to change our appetite-regulating hormones –it takes generations. And we haven’t changed our dietary habits, because…it’s tough; even when we try, it’s seems to be futile; we lose the hard-won gains despite our heroic efforts. Why?

My brain made me do it

The reflexive response to people who fail their diet is –try harder! Where is your willpower? I used to believe that these people are a product of a permissive culture that demanded little self- discipline, biology notwithstanding. Mea culpa: accumulating evidence tells us that biology still
reigns supreme.

In an article titled Long-Term Persistence of Hormonal adaptations to Weight Loss (New England Journal of Medicine, Oct.27, 2011) researchers from the University of Melbourne tested all the known hormones that regulate appetite. Among the most important ones are leptin, ghrelin , peptide YY, amylin and cholecystokinin (CCK). Leptin is secreted by fat cells, or adipocytes, and is an indicator of energy stores; it acts on the hypothalamus, a region deep in the brain that contains the center which receives the signals from different hormones and regulates appetite accordingly. A drop in caloric intake causes a large drop in leptin secretion, and an increase in appetite. Grhelin, which is secreted by the stomach, signals the state of distension of the stomach –an empty stomach causes a large increase in circulating grhelin, and an increase in appetite. Amylin is secreted from the β cells in the pancreas, the same cells that secrete insulin. After a meal, the circulating levels of both hormones go up, and as the nutrients are absorbed by the tissues –their circulating levels drop. A drop in amylin then signals to the hypothalamus “need more nutrients”, which is translated in the brain to the sensation of appetite.  Same is true for CCK, which is secreted by the pancreas and is sensitive to the fat content in the diet, and peptide YY, secreted by the small intestine. In short, an array of hormones constantly monitoring the nutritional state of the game and telegraphing their messages to the hypothalamus. So you can already see that it would be hard to sneak by these sensors of nutrition; they cover the gamut. This is probably the reason that attempts to manipulate the levels of leptin
(up) or grhelin (down) so as to fool the appetite center in the hypothalamus, resulted in merely transitory appetite suppression; the other hormones continued to transmit hunger signals.

Still, there was the hope that with prolonged dieting these hormones will finally adjust to the new metabolic reality and send their signals to the brain with less urgency, so to speak. The hope was that leptin will eventually come back up, grhelin will stay down, and so on, as the lower caloric intake persists over weeks and months. No such luck: the NEJM paper showed that the appetite hormones maintained their original, pre-dieting levels, for at least 12 months (the length of the study). Is it any wonder that dieters describe their frustrating experience as a never-ending battle?

What’s to be done?

With such metabolic heavyweights arrayed against weight-loss, do we throw our hands up? Not at all. There are myriad studies of effective strategies for losing and maintaining weight loss. The principles are simple:

  1. You need to lose more  calories than you take in. You can guess where I am going: exercise. I can’t  emphasize its importance. Not only is exercise heart-healthy, it is diet -friendly  as well. There are some fringe benefits that are not restricted to  calorie-loss. Exercise releases endorphins and enkephalin, as well as  endocannabinoids. The first two are the natural equivalent of morphine,  the third has the same effect as marijuana. No wonder regular exercisers  report a sense of well-being, even euphoria, when they exercise. And  happier people tend to eat less, to boot.
  2. Most controlled studies  find that the most effective diets have a high protein and a low glycemic- index content. And you don’t have to avoid all carbohydrates – such punishment  is unnecessary. You can fill your low glycemic- index portion with fruits,  vegetables and fiber.
  3. Get frequent and  continuous feedback. You can do it with an online support group, a buddy,  or your bathroom scale. Daily weigh yourself, and if you see the beginnings  of an upward creep- don’t delay, bring the weight down ASAP. The longer you wait, the tougher it will get.

Bottom line: it is what it is –you can’t change millions of years of natural selection. But you can change your lifestyle. After a while it becomes second nature, and a happy one, too.


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.


Please enter your comment!
Please enter your name here

This site uses Akismet to reduce spam. Learn how your comment data is processed.