It is a well-known phenomenon: People under stress hit the fridge and gorge on candy and fatty food. A gallon of ice cream in one sitting is not unheard of. But people who think deeply about such things asked themselves: Why don’t they (people under stress) gorge on veggies? And what is the nature of the connection between stress and obesity? Is it simply overeating = obesity, or is there a deeper connection, involving the brain? After all, stress is a mind thing.

 

The physiology of acute stress

Almost every physiological action in our body is controlled by two systems: the autonomic nervous system and the endocrine system.

The autonomic nervous system has this name because it is, well, autonomic; it marches to its own drum, if you will, independently of our whims, wishes, or commands. This system is made up of two subsystems: the sympathetic and the parasympathetic. Basically, they are the Yin and Yang of the autonomic nervous system. The sympathetic nerves secrete noradrenaline, a close relative of adrenaline, and it does everything you’d expect it to do. It accelerates the heart rate, increases blood pressure; in short, it readies the body to react to acute stress situations. My favorite example: You spot a lion coming at you. You want to supply ample blood to your muscles so you can run for your life, or if you are foolish enough, fight the lion; hence, the increase in heart rate and blood pressure. The parasympathetic system secretes the neurotransmitter acetylcholine, and it has exactly the opposite action—it slows down the heart and reduces blood pressure.

The endocrine system reacts to stress by releasing two “stress hormones”: cortisol from the brain and adrenaline from the adrenal gland. Their action is similar to that of the sympathetic nervous system—increase blood pressure and heart rate.

 

The other type of stress

So far so good; but how does increased heart rate cause obesity? The answer is it doesn’t. What I just described is the response to acute stress, and our bodies are well-adapted to handle it. But modern life added another type of stress: chronic stress. And here, a peptide called neuropeptide Y, or NPY, comes into play. Its existence has been known for several years, but its function was largely unknown. It is expressed throughout the brain but is especially abundant in circuits that regulate feeding and response to stress. Not surprisingly, like many other brain hormones, it is also secreted in tissues outside the brain that are involved in metabolism; it is secreted by sympathetic nerve endings in adipose tissue. Its function there has only recently been defined by Kuo and his coworkers. It increases adipogenesis (formation of fat tissue) by triggering both the formation of new adipocytes (fat cells) from immature preadipocytes and by increasing the blood supply to the adipose tissue by the formation of new blood vessels (a process called angiogenesis).

Even more intriguing is that the new fat tissue was not formed just anywhere in the body; it was formed in the abdomen, and specifically around the internal organs of the abdomen. This is exactly the fat distribution that is implicated in the genesis of metabolic syndrome. And to clinch the case, it does it only under severe chronic stress conditions. When mice were subjected to 2 threatening and severe chronic stress protocols, they secreted NPY; when they were subjected to non-threatening mild stress, no NPY was secreted. In biological experiments, demonstration of a relationship between the “dose” (e.g., severity of the chronic stress) and “response” (e.g., secretion of the peptide) lends credibility to the observation, simply because, in biology, almost everything is dose-dependent.

 

Why do we prefer sweets and fats?

The mice in the experiment secreted NPY only if allowed to eat fatty or sugary food. Regular mouse chow did not support secretion of the hormone even under severe chronic stress conditions. We know that high-calorie food triggers the reward circuits in the brain. In fact, chronic feeding of high-calorie foods activates all the circuits and brain centers that are involved in addiction. That, in turn, induces more eating, which increases the degree of addiction, which…you get the drift. Bottom line: obesity.

The details of the connection between secretion of NPY and high-calorie food still need to be worked out. Why didn’t regular, low-calorie food have the same effect? What are the specific neural circuits involved in this calorie/reward/peptide axis of evil? What is the mechanism for the specific accumulation of fat around internal organs? Will withdrawal of high-calorie food result in reversal of the accumulation of fat back to normal?

Obviously, many unanswered questioned are triggered by this research. But this is the hallmark of good science: Every answer raises many more questions.

 

In summary

NPY is the link between stress and obesity. Its action:

  • Secreted from the sympathetic nervous system only under conditions of chronic severe stress,
  • Increases adipogenesis by triggering adipocytes formation from preadipocytes, and by increasing blood supply to the adipose tissue,
  • Secreted only when high-calorie diet is available,
  • Involves the activation of reward circuits in the brain,
  • And last but not least, it induced a state of metabolic syndrome (obesity, insulin resistance) in the experimental mice.

 

What is the relevance of this research to human obesity/metabolic syndrome?

Obviously, this phenomenon needs to be demonstrated in humans. Demonstration that NPY levels are markedly higher in chronically-stressed individuals will be a big step forward. Inhibition of secretion of NPY through drugs or stress reduction techniques will add weight to the hypothesis.

The demonstration of weight reduction through reduction of NPY secretion will be a boon to us and to our strained healthcare budget.

Here is a thought that may have occurred to you. Can our increasingly stressful lifestyle be partly responsible for the obesity/metabolic syndrome epidemic?

Here is another thought. Rather than wait for the results of these experiments to yield the ultimate proof, why not toss out all the sweets and high-calorie foods, and stock the fridge with “good for you” veggies? No activation of the reward system in your brain = no NPY secretion. A not very appetizing solution, I know. I’d rather wait for the results of the human experiments and then decide.

 

Epilogue

My estimate is that to carry out the required experiments in humans would cost about $10-20M. To develop and clinically test an NPY inhibitory drug could cost anywhere from $50-100M. Can the healthcare mavens quickly calculate what would be the ROI (return on investment) on this sum?

3 COMMENTS

  1. Interesting article. I am not a doctor, but have anecdotal experience (my own) of losing 26 lbs simply through acquiring two very high energy sheep-herding-type dogs (English Shepherds). We walk 6-8 miles per day in winter and summer, more like 8-10 miles in fall and spring–4 walks, 2-2.5 miles a piece. Been doing this for 4 years now–what is interesting is that my refrigerator has now been reconfigured, and I’ve dropped all the high-calorie stuff–simply because my body is no longer interested. Any literature on breaking the cycle you identify with moderate, sustained exercise done periodically through the day and its impact on human desires for the high nutrient foods? I wonder if the amount and regularity of the exercise I’m getting through the day is having a similar effect as calorie restriction? Incidentally, while 8-10 miles of walking may seem like alot, it takes about 2.5 hours, all totalled–which is what I wasted regularly in mindless activities when I was a couch potato.

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