Biological Energy - Too much of a Good Thing?

The COVID-19 15… As we all begin to emerge from this unprecedented time of sequestration, many of us have found that the lack our normal daily activities, and perhaps more regular access to the fridge, has resulted in the accumulation of a few extra pounds. Weight gain is, of course, another term for the expansion white adipose tissue (WAT), the primary fat organ in animals. WAT is composed of adipocytes, cells characterized by a large, internal lipid droplet. In this droplet, triglycerides, the primary energy storage molecules, are held until the animal requires energy. Due to the intricate communication channels between the fat organ and other organs and the musculature, triglycerides are released during times of energy demand and undergo β-oxidation to provide ATP.

But that is the second half of the story. The first half comes from the sun’s relentless bombardment of the earth with more than a petajoule (1E18 joules) of electromagnetic energy every second. That energy drives the emergence and persistence of plants that, when consumed by animals, pass along that captured energy in the form of glucose. Consumed glucose is converted into ATP through glycolysis and oxidative phosphorylation and drives the persistence of the animal. If the animal’s immediate energy needs are satisfied, the excess glucose is converted into triglycerides through the fatty acid synthesis pathway and incorporated into the lipid droplet in adipocytes with the help of insulin.

Triglycerides are a composite molecule composed of three fatty acids esterified to glycerol backbone. Each of the three fatty acids can contain a different number of carbons (from 4 to 28) and can have a range of double bonds (from 0 to 5). In the exquisite efficiency of biology, those fatty acids can have independent bioactivity (meaning it can perform an independent biological function) or they can be oxidized into usable energy (ATP). We currently do not have much understanding for why certain fatty acids are generated (there are over 50 unique fatty acids) and stored in triglycerides nor do we know if there is any significance in the ratios of fatty acids in triglycerides. We also don’t know if the content (e.g. the specific fatty acids) of triglycerides varies with different disease states but we do know that higher levels of triglycerides in the blood indicate that something is awry with the metabolism of the system.

Which brings me back to the COVID-19 15. What’s the issue with a few extra pounds? Isn’t it a good thing to have more on-board energy? As with most answers in science, it depends. There are some people who carry excess weight and appear to be metabolically fit and healthy. There are people who have a healthy BMI but develop serious negative health outcomes. Diving a little deeper into the biology may help to shed some light or provide some guidance for areas of biomedical research. Adiposity (increasing the fat pad mass) happens through hyperplasia and/or hypertrophy. In hyperplastic growth, increases in fat mass occurs through a proliferation of adipocytes (cells), each with its own lipid droplet containing triglycerides. Hypertrophic WAT growth is the engorgement or swelling of each, individual adipocyte, much like filling a water balloon. Early research suggested that hyperplastic growth occurred only in fetuses and infants and that the majority of adiposity in adults was through hypertrophy. More recent research suggests that hyperplasia can happen later in life, but that hypertrophic growth is the primary mechanism for adiposity.

Although it is still an open question, the different types of adipose tissue growth may impact health in different ways. We do know that hypertrophic growth can led to certain detrimental health consequences. It has been shown recently that women of normal BMI who developed breast cancer had pockets of hypertrophic breast fat (1). Due to the swelling of the fat cells, blood supply to the tissue is choked off and leads to hypoxia, necrosis, and inflammation in the tissue. These pockets of “angry fat” may lead to a greater probability of the emergence of cancer. We also know that adipocytes can reach a maximum expansion size and will start to “turn away” triglycerides and fatty acids. This can lead to higher levels of triglycerides and fatty acids in the blood where they can take up ectopic deposition in other organs. As fatty acids are toxic to cells other than adipocytes, this deposition can lead to necrosis and inflammation in the tissue.  

As an endocrine organ, WAT communicates with many other organs, such as the pancreas, liver, kidneys, and brain, as well as the musculature through signaling molecules called adipokines. Increases in the fat mass pad increases the “volume” of the adipokine messaging, including stimulation or suppression of energy management. When energy reserves are running low, adipokines release signals that drive feeding behaviors and energy conservation strategies. As energy levels rise, signaling of satiety arise and energy strategies normalize. Under conditions of chronic excess energy input, and subsequent hypertrophy of the adipocytes, signaling to organs like the pancreas may include signals to stop producing insulin to stem the transportation of triglycerides into the engorged adipocytes. In addition to elevating triglyceride levels, the reduction in insulin can lead to high glucose levels and potentially to metabolic disease such as diabetes.  

The COVID-19 15 may have different impact on different people depending, in part, on how the excess energy is stored. At a minimum, increased weight leads to more wear and tear on the system. In more extreme cases, critical increases in the on-board energy reservoir or potential, manifested in increased adiposity, often leads to chronic health conditions such as metabolic syndrome, heart disease, and cancer. Understanding the dynamics of how the energy reservoir within a person impacts the overall function of that person is a central area of biomedical research. And understanding energy mechanisms of the body will lead to critical new health interventions for the obesity epidemic that is sweeping the globe. In the meantime, it’s probably a good idea to get out there and shed those extra 15.

1. The association between DXA-derived body fat measures and breast cancer risk among postmenopausal women in the Women’s Health Initiative. Arthur, RS, et al. Cancer Med. 2020 Feb; 9(4): 1581–1599.