An Exercise Pill for Couch Potatoes

Sep 22

by Sachin Aryal

On a recent flight returning from the American Physiology Summit, I was seated next to a gentleman who was unfortunately not comfortable in his economy class seat due to his large size. We began chatting, and he told me that his doctor had diagnosed him with metabolic syndrome and that he hated exercising, although he was told that exercise would help him. I asked him if he would like to take a pill as a substitute for exercise. He was all ears.

Like this gentleman, there are millions of people around the world who are unable to exercise due to many reasons, such as ill health and physical limitations. Such individuals are more prone to metabolic syndrome, a condition which often presents high blood pressure, high body weight, high blood sugar, high bad fat in the blood, and a very low level of a biochemical in our blood called β-hydroxybutyrate (BHB). BHB is a ketone body that our bodies generate at a high level during exercise. This is to meet the increasing need for energy.

Our body normally uses glucose as a source of energy. But during intense exercise, when glucose is used up, we tap into using stored fats in our bodies to meet the demand in energy. When fats are broken down, BHB is formed. Intriguingly, we and others have found raising BHB in our blood has profound beneficial effects on blood pressure and body weight. Luckily, we found an FDA-approved chemical called 1,3-butanediol (BD), which, when consumed, converts into BHB. Therefore, I asked whether nutritional supplementation with BD could be used as a simple substitute for exercise. The sheer thought of this being a successful study brought a chill to my spine, thinking about my research yielding a solution to help folks like my plane friend.

For my experiment, I used rats, which are known as the low-capacity runner (LCR) rats. Unlike their healthy counterparts, which love to run on a treadmill, these rats are “couch potatoes” which do not care to run when introduced to a treadmill. Earlier work has shown that the LCR rats are prone to metabolic syndrome. So, they were perfect as models to test my hypothesis that feeding BD would lower their metabolic syndrome. I used two groups of LCR rats. Water given to only one of the groups was spiked with BD. The study went on for 9 weeks, during which I monitored their blood pressure and body weight periodically. Blood pressure of rats was monitored continually via a surgically implanted radiotelemetry device into their major blood vessel, the aorta. At the end of the study, I humanely euthanized the rats through approved protocols and collected their organs for further study.

My expectation was that the rats administered with BD would have lower blood pressure and body weight. During the early two weeks of this experiment, I was rather disappointed because both the groups of rats with or without BD treatment had similar blood pressure and body weights. But the eureka moment was in week 9 into my study when I observed that the rats administered with BD had significantly lower blood pressure, blood sugar, and body weight compared to the rats that were not given BD. My happiness knew no bounds! I knew at that moment that I had discovered something that would hopefully one day help folks like my plane friend.

But an important question remained. How? How did BD work? For the first pass, we checked whether the animals receiving BD did elevate BHB. Yes, they did, and that was good. But how does BHB operate to lower blood pressure and body weight? This is currently my ongoing research work. So far, we are convinced that one of the ways by which BHB operates is deep within the cells of our bodies, inside the cell nuclei, where it binds to specific proteins that serve as spools for our DNA. These proteins are called histones, and the process of BHB binding to histones is called histone β-hydroxybutyrylation. What happens next is fascinating. I found that by binding to histones, BHB causes these “spools” to specifically open at certain spots, whereby the “thread” or long chain of DNA opens, and the genes located within these open regions of DNA are then decoded to make proteins which break down fat. This explains why the rats given BD lowered their body weight. But how does this process lower blood pressure, too? This is the question that I am currently working on towards my PhD thesis.

Our bodies are amazing machines, the parts of which are called “anatomy,” and the way the parts work in complex ways is called “physiology.” I am proud to call myself a researcher in this field of medicine, which connects the dots and lets us understand the secrets of our bodies from form to function. From my experience thus far, the thrills and spills of research swinging from disappointments to excitements as the answers to my research questions unfold are ones that I would never give up. The bonus is the thought that one day my work could help improve the quality of life of some people like my plane friend.

Back to my conversation with my co-passenger on the plane ride, he was fascinated with my research and asked if he could get some BD. Well, that was beyond my capacity, because I am only a researcher working with pre-clinical animal models. There are strict regulations whereby further experiments must be conducted in human clinical trials before federal approvals can be obtained for BD as a supplement to correct metabolic syndrome. When that day dawns, I know that I will experience priceless joy for having contributed my small might to make it a reality.