Can Drugs Mimic Exercise??

Ancient humans were hunter-gatherers who moved endlessly in the search for food as well as going long periods without food. This resulted in an evolutionary process that strongly favors food storage, primarily as fat but also in liver and skeletal muscle as glycogen (polymer of the sugar glucose). The consequences of our evolution are that humans have developed an essentially endless capacity to store excess food intake as fat. However, it is not the excess fat, in and of itself, that kills but the negative effects of excess fat accumulation on the functions of critical organs. In the modern world humans don't need to forage for food, and in fact humans no longer consume food solely for the benefit of survival, humans consume food nearly exclusively for the pleasure-reward benefits. We need not walk to get food but simply get in our cars and drive, and as a result, the absence of daily exercise has resulted in a global epidemic of obesity and obesity-associated diseases. A study conducted in 2015 indicated that the United States alone is about 5 billion pounds overweight and is a population (along with the rest of the industrialized world) heading into a non-reversible medical catastrophe. And the sad thing is that the epidemic can be prevented and reversed, at no expense to the individual, by a simple mechanism: physical exercise.

Exercise induces weight loss because skeletal muscle prefer to burn fat for their energy needs and so exercising increases the rate of fat metabolism. The biochemistry may seem complex to the uninitiate but basically the human body has a LARGE number of skeletal muscle cells all of which can burn up large amounts of fat in the process of making energy which in cells is the nucleotide, ATP. This compound of raw biological energy is made inside a small "factory" inside almost all cells in the body called the mitochondria. Red blood cells do not contain mitochondria. And skeletal muscle cells are reddish in color because they are loaded with the energy producing "engines". Exercise also results in increased numbers of mitochondria inside each skeletal muscle cells leading to even greater capacity to burn up fat. Thus, the benefits of exercise from solely the perspective of weight loss. Of course exercise has numerous other benefits like strengthening the heart, making ones bones harder, and increases brain activity. 

But we all know that Americans, in particular, seem loathe to carry out any level of physical activity. So is one answer to this epidemic the development and prescription of drugs that mimic exercise? Numerous chemical compounds, some of which are available naturally in various types of plants, have already been shown to exert effects on skeletal muscle metabolism that mimic real exercise, in other words purportedly allowing one to lose weight without lifting a finger. Indeed several of these compounds have been used, and subsequently banned by the World Anti-Doping Agency, as performance enhancing agents.

So what are these potential exercise-free weight loss "drugs"? Think red wine, the natural compound in red wine called resveratrol is one such compound. Another natural compound is nicotinamide riboside (NR) which is a form of vitamin B3 (niacin) found in the body in response to the normal metabolism and use of the bioactive forms of vitamin B3. Another naturally occurring compound, which is an intermediate in the pathway by which cells make some of the building blocks (nucleotides) of DNA and RNA, is the compound designated AICAR (long full name not relevant for this discussion). Several man-made chemicals with the designations GW501516, R419, and GSK4716 belong to this family of exercise mimics. All of these natural compounds and man-made chemicals have as a common outcome, an induction of mitochondrial biogenesis (making more mitochondria) and dramatic increases in fat metabolism. It is important to point out that GW501516 and AICAR have been banned for use by competitive athletes.

At the molecular level resveratrol, AICAR, and R419 enhance the activity of the global metabolic regulatory enzyme known as AMP-activated protein kinase (AMPK). This enzyme, as the name kinase implies, adds phosphate to its hundreds of protein substrates. The result of AMPK activity is inhibition of processes in cells that consume ATP in favor of increased activity of pathways that lead to the production of ATP by the mitochondria. One of these pathways is fat metabolism. Increased fat metabolism means increased fat loss, thus weight loss. You can read more details on the activities of resveratrol (and other natural AMPK activators) in my Supplement Science website as well as the many functions of AMPK in my Medical Biochemistry Page website:

http://supplementscience.org/resveratrol.html

http://themedicalbiochemistrypage.org/ampk.php

What is the TAKE HOME message here?? It is indeed possible to enhance athletic performance with these natural and man-made compounds. However, to assume that using these compounds solely for the purposes of weight loss WITHOUT any form of physical activity will prove futile and be of very little health benefit without first changing ones diet to reduce caloric intake. In addition, exercise provides so much more health benefits than weight loss alone. It may seem daunting to someone who is overweight or obese to consider exercise but a simple walk around the block, or walking up an down the stairs at home a few time is all it takes to get started.

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