⚕️ » The Evolution of Metabolic Regulation in Animals: A Comprehensive Breakdown with Dr. Bob Melamede

Over evolutionary time, a clear trend can be seen in the increasing complexity of organisms – from ancient and simpler organisms such as bacteria to highly complex organisms such as modern mammals. While the process of evolution is often boiled down to just “survival of the fittest”, such a simplification might not be very useful in understanding the driving force behind this increase in complexity. Instead, many researchers in recent years have sought to explain the rise in complexity as the result of metabolic requirements and the need to regulate metabolism. The energy produced by a cell is used primarily for gene expression and protein synthesis, so the more genes and proteins a cell makes, the more energy it will need. Simple organisms such as prokaryotes (cells without a true nucleus, such as bacteria) are constrained in terms of how much energy they can produce and so are limited to how many genes they can express and how many proteins they can make. Eukaryotes (cells with a nucleus, such as mammalian cells) have mitochondria that act as “power stations” and produce massive amounts of extra energy that can be used to express many more genes and thus make many more proteins. Thus we can see that the major evolutionary increase in complexity from simple organisms (bacteria) to complicated organisms (mammals) is associated with increased energy metabolism.

A primary driving force in the evolution of complexity is gene duplication, which can occur through many different processes as pieces of DNA are copied and shuffled around over generations. This can be likened to the car you drive to work every day. If you just have the one car, then you cannot do anything too drastic to that car or else it might not work properly and you won’t be able to get to work. Thus you will be constrained to using that car just for your essential activity of getting to work every day. If, however, you were to acquire a second car, then you would be free to experiment with that car because it would not be needed for commuting to work every day. You could try to make the car faster, or more comfortable, or more fuel efficient. You could even modify its function by using the car’s drive train to run a generator to produce electricity, which would allow you to do all kinds of things that you couldn’t do when all you had was your car for commuting to work. Thus gene duplication frees genes from selective pressure and allows the duplicated genes to be mutated and modified to carry out new functions. In a similar way, the acquisition of new genes with new functions has allowed organisms to develop new ways of producing and regulating their energy production in order to allow them to carry out ever more complex biological processes.

In addition to the presence of mitochondria, a major evolutionary leap between prokaryotes and eukaryotes is what is known as the nucleosome. While all cells have means of packing their genetic material into the cells, eukaryotes have special proteins that wind up the long DNA molecules and control access to the genes in the DNA. This adds an entire extra level of regulation of gene expression because the proteins that control access to the genes can be modified at different times in the cell’s life cycle to turn different genes on or off. Thus we can see that the increase in the number of proteins that modify these nucleosome proteins (again through gene duplication events) adds increased functional diversity and allows the organism to engage in more complex activities.

All living cells must maintain energy balance in order to survive, and if an organism does not take in a sufficient amount of food it will die. Regardless of whether the organism makes its own food, as in the case of plants, or must eat something else, the molecules in that food are all converted to a form that can be used by cells. The basic unit of energy in the cell is ATP (to remind us that these are “food” for cells, we called them “ATPizzas” in high school biology class). These energy-containing molecules are produced by different chemical reactions depending on the food source, but in the end the same molecules are produced that can be used by all cells in the body to grow and to carry out all of the processes necessary for sustaining life.

Because ATP molecules are used in all cells, there must be a way of sensing ATP levels in the cell so that the cell knows if it is starving or if it is well fed. The most evolutionarily ancient energy sensor in the cell is the AMPK/TOR pathway. When ATP levels are low, in other words, when the cell does not have enough food, AMPK turns off processes that require ATP and instead turns on processes that begin to recycle and reuse cellular components instead of making new ones. In contrast, TOR is active when ATP levels are high, in other words, when the cell is well fed, and thus TOR turns on processes related to growth and other energy-consuming activities. Thus the regulation of the AMPK/TOR pathway is fundamental for all cellular processes, and this regulation has increased in complexity over evolutionary time. A prime example of this is insulin, which turns off AMPK and turns on TOR, and the complexity of the insulin-signaling has increased over time – from lower animals that have only a single insulin receptor to mammals that have multiple insulin receptors and thus can better fine tune the activity of the AMPK/TOR pathway to ensure the most efficient use of their cellular energy production. Thus, again, we see that gene duplication events have increased the regulatory complexity in organisms over time.

Even further levels of complexity have emerged over time as organisms have developed greater needs for functional diversity. In animals, molecules such as adiponectin and leptin interact with AMPK and regulate appetite, food intake, and metabolism, and there is a clear increase in the diversity of these molecules along with evolutionary complexity; for example, leptin is currently only known to be produced by vertebrate animals. In higher animals, thyroid hormones act as a master regulator of metabolic processes by interacting with molecules such as leptin and insulin, and the number of different thyroid hormones has increased in more complex organisms leading to greater diversity of metabolic effects. As yet another layer of complexity, all of these regulatory molecules in higher organisms interact with the nervous system to regulate the production and use of cellular energy stores. 

These evolutionary changes in the regulation of energy metabolism have led to the development of entire biological processes that allow organisms to respond and adjust to changes in their environment. This phenotypic plasticity allows the organism to regulate its energy production and use in order to adjust its metabolism in response to changes in the environment such as pH, temperature, food and water availability, and so on. Thus increased metabolic complexity leads to responses such as hibernation as seasonal variations in food supply change, changes in muscle mass in response to exercise, seed production as light levels change, and so forth. All of these adaptations are possible because these environmental cues lead to small changes in energy availability and energy needs that are detected by the regulatory systems that are in place, and the more complex these systems, the more complex the response to changes in the systems. These changes can occur not only within single cells reacting to seasonal changes over the course of their lifetimes, but can also occur in response to environmental changes experienced by parents that affect the characteristics of their offspring. Ultimately, such plasticity can become permanent as seen in the evolution of endothermy, or “warm bloodedness”, where broad metabolic changes have taken place to allow organisms to shift energy production from repair and growth processes to the production of heat and thus allow the organism to maintain high levels of metabolic activity regardless of environmental conditions.

The increasing complexity of metabolic regulation over evolutionary time, through gene duplications and modifications to different proteins and systems, has accompanied the evolution of ever more complex organisms. Such processes can also be used to explain global biological phenomena such as life histories, ecosystem changes, migrations, and so on. All of these things rely on the increasing layers of regulatory complexity that allow organisms to engage in more complex behaviors. Thus it is becoming ever more apparent that metabolic regulation is one of the primary driving forces in the evolution of biological complexity over time and that the notion of metabolic complexity can be used to understand almost all biological activities. These concepts are particularly relevant to modern humans, who have evolved highly complex metabolic regulatory systems that are fine-tuned to work in response to the high levels of exercise and to the foods available to our Neolithic ancestors. Modern sedentary lifestyles and the availability of energy dense but nutritionally deficient foods thus represent significant perturbations in these systems leading to negative outcomes such as obesity, type 2 diabetes, and other metabolic diseases that have reached epidemic proportions in recent decades.

Dr. Bob

Dr. Robert Melamede has a Ph.D. in Molecular Biology and Biochemistry from the City University of New York. Dr. Melamede is a recognized leader on the therapeutic uses of cannabis, and has authored numerous papers on a wide variety of subjects. Dr. Melamede retired as Chairman of the Biology Department at University of Colorado, Colorado Springs in 2005, where he continues to teach and research cannabinoids, cancer, and DNA repair.

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Dr. Bob

Dr. Robert Melamede has a Ph.D. in Molecular Biology and Biochemistry from the City University of New York. Dr. Melamede is a recognized leader on the therapeutic uses of cannabis, and has authored numerous papers on a wide variety of subjects. Dr. Melamede retired as Chairman of the Biology...