The Biochemistry Behind Appetite Regulation
Our appetite is one of the core biological behaviors we need to engage in. It is based on and controlled by not only physical demands but by a strong evolutionary drive.
However, our current landscape looks incredibly different in terms of access to foods than it did millions of years ago.
This poses a problem to our modern society because our neural mechanisms are not always consistent with what our bodies have evolved to expect.
Our species evolved in agricultural societies. As humans, we evolved during famines, floods, and countless other natural disasters.
However, our population remains dense. There are billions of us on this planet. And that is due to the fact that we have been able to compensate for what our species experienced millions of years ago.
Today, we don’t live with those uncertainties. We can predict and prepare for disasters like these, we produce unimaginable quantities of food, and many of us who are fortunate enough, have constant access to it.
Yet, our bodies still operate on those basic biological drives. One that is not always beneficial in a society thriving off of high-calorie diets and low activity lifestyles.
We are leading lives with easy access to anything we might need, and protection from the dangers we once faced.
We are already in a situation of massive public health failure. As Americans, we have allowed individuals in society to function within a system that has failed them.
But the question remains — how did we get here?
Many of you have likely heard of the term metabolism. Although we might not have an exact definition for it, we know to correlate it with certain types of people.
“Oh, she can eat whatever she wants and stays skinny. She has a fast metabolism.”
But from a purely chemical, physical, or rather, biological perspective; what is metabolism?
The concept of our metabolism is quite simple; it’s the breaking of chemical bonds in our food, which releases energy to be used by our body.
Specifically, food and beverages are the only way we can make this energy. Unlike plants or other organisms, we can’t get our energy from other sources, such as the Sun.
When our body digests these foods and beverages, we break chemical bonds, thus releasing the energy stored within.
As humans, we have a constant requirement for energy. Whether we are sleeping, or in a coma, we require energy to stay alive.
When we consume food, about a third (33%) of the calories we consume are simply devoted to digesting, metabolizing, and absorbing nutrients from our food. We refer to this as our TEF or our thermal effect of food.
A small component of this is also due to certain calories that we simply cannot absorb, such as non-digestible fibers. However, fiber has a large role in how we establish our metabolism. From a caloric perspective, fibers are superfluous. As we will see later, our bodies have evolved to expect heavy amounts of fiber within our diets. When we consume little fiber, our body’s biochemistry changes.
In addition to calories used to break down our food, 55% of the calories we consume are used just to keep us alive. It is used to fuel processes like maintaining a core body temperature, our heartbeats, our lungs’ intake of oxygen, etc. These calories are not used in any active behavioral processes. They are used to establish our resting or our basal metabolic rate (BMR); the energy we burn with absolutely zero physical activity.
When we take into account our TEF (33%) and BMR (55%), that leaves us with just 12% of the calories we consume being devoted to our physical activity.
Once we understand metabolism, we can begin to look at what happens to our bodies when we eat certain foods.
Our diet consists of macromolecules; different types of calories and foods we intake. Other than the water within our foods, we find carbohydrates, fats, proteins, vitamins and minerals, and non-digestible fibers.
Our Bodies Love Carbohydrates…
Our bodies love carbs.
Despite all the news we hear about low-carb diets, keto diets, and avoiding carbs at all costs, carbohydrates fuel us, providing us with the most immediate source of energy.
We ingest two different types of carbohydrates: complex carbs (fruits, vegetables, whole grains, etc.) which your body works harder to break down into glucose, and simple carbs (candy, soda, sweets, etc.) which provide your body with instantaneous energy.
Glucose is a 6-carbon ring and is actually your body’s preferred energy source. Every single cell in your body can utilize glucose as a source of rapid energy.
Evolution designed our bodies to withstand long periods without food consumption; we never knew when the next meal would be. Therefore, when we eat, we consume foods in excess than our body requires at that very moment. Not only do we replenish energy stores, but we also save some extra.
As our bodies digest these carbohydrates, the glucose within is liberated and absorbed by the blood. This results in heightened blood sugar, or blood glucose.
However, the sugar within the blood is no good for the cells. In order for the cells to utilize the glucose as energy, it has to move inside the cells. The heightened blood sugar stimulates the pancreas, and the beta cells in the pancreas respond by secreting insulin, a hormone that promotes the absorption of glucose from the blood into the liver, fat, and skeletal muscle cells, and regulates our metabolism. Once the insulin promotes the uptake of glucose by the cells, our blood sugar is once again lowered.
There are two target tissues that take up a majority of our glucose; the liver and the muscles. When insulin is available, it converts glucose into glycogen, strings of glucose molecules that are strung together. Glycogen serves as a form of short-term energy storage available from the liver and the muscles.
For example, if you have just eaten breakfast, you will have a higher glycogen storage. But 4 hours after eating, your blood sugar levels will have dropped. When the blood sugar levels are low, the alpha cells in the pancreas produce glucagon, a hormone that promotes the breakdown of glycogen into glucose in the liver and muscles. Glucagon will liberate the glucose out into the blood so that it can be utilized and the blood sugar remains stable.
Not only do we consume fats directly in our diet, but we also receive fats from surplus sugars. When we eat excess amounts of carbohydrates and fill up our glycogen stores, the excess carbohydrates are converted into fats.
When carbohydrates are consumed, the glucose is liberated and the insulin secreted by the pancreas converts glucose into glycogen. This process is called glycogenesis.
In between meals, glucagon stimulates the breakdown of glycogen in order for the glucose to be released and maintain a stable blood sugar, which is called glycogenolysis.
Insulin along with leptin, a hormone produced by the fat cells, serve as satiety cues and signal to the brain that you are full after eating a meal.
Insulin and leptin tend to move together. Insulin, produced in the beta cells pancreas, and leptin, produced by the fat (adipose) cells, tend to move together. Insulin stimulates fat cells to convert excess glucose into fat. This signals to the fat tissue that the body has adequate nutrition at the given moment and will release leptin, making you feel full.
Meanwhile, lipolysis, the breakdown of fat, occurs when leptin levels are generally low. This generates many different types of energy sources.
Fat can either break down into glycerol or free fatty acids. The body uses glycerol to produce glucose in the liver, while free fatty acids serve as fuel for the organs; they can be utilized by any part of the body outside of the peripheral nervous system. These free fatty acids, produced in the liver, can also be ketone bodies, a form of free fatty acids that can be used as fuel for the brain.
Fat is a very important energy reservoir for the body. There is almost an unlimited capacity for energy storage through fat. An individual can store much more fat, than they can glucose, as glucose storage is limited. In addition, when fats are broken down, they generate more than one energy source, which proves to be immensely useful to the body.
The Building Blocks of Proteins
The proteins we consume are essentially broken down into 20 different amino acids. In order to sustain life, our body requires all 20 of them, although not all of them are considered “essential.” 9 of them can only be acquired through our diet; our body does not have the capability to produce them. The other 11 can be manufactured by our cells even when they are not part of our diet.
However, what makes proteins different from fats or carbohydrates is that we can’t store them as glycogen or fat. Our cells use proteins for cellular processes, but we cannot store the amino acids. The excess proteins we consume are broken down and excreted unless we are in extreme starvation, and our body does not have enough other food sources. In that case, our bodies will break down muscle, a process called gluconeogenesis, in order to use the amino acids to make glucose.
Energy Sources and Utilization
Since our bodies require a constant source of energy, but not an endless supply of food, it is crucial for us to be able to store these excess surpluses of macromolecules.
Insulin plays one of the most important roles in energy utilization. Without insulin, our bodies cannot utilize the glucose in our bloodstream, which leaves our energy stores depleted.
However, the brain isn’t involved in this process; it has evolved to use glucose directly, without the need for insulin. Our brain is the most energetically selfish organ in our bodies. If we’re low on glucose, it’s all going to the brain, instead of the rest of the body.
The body is powered differently when it is in a fasting state; when it’s been approximately 4 to 5 hours or longer since your last meal.
The glucagon hormones produced by the alpha cells in the pancreas stimulate the breakdown of glycogen, and any remaining amino acids in the body are also converted into glucose. The liberated glucose and ketone bodies power the brain, and fuel muscles where more stored protein is broken down into amino acids. Lipolysis which occurs in fat, known as adipose tissue, releases free fatty acids, which are then converted into even more ketone bodies and glycerol in the liver. This inhibits the secretion of leptin, a hormone that sends satiety cues to the brain, which causes your brain to send you pangs of hunger.
Hypothalamic Energy Regulation
Our hypothalamus serves as our master endocrine gland, controlling many of the hormones involved in appetite regulation.
The arcuate nucleus, on the lower right of the image on the left, serves as the receiving station for many hormones. In the middle of the arcuate nucleus is a small white triangle, representing a fluid-filled cavity which is referred to as the third ventricle. This allows for cerebrospinal fluid to flow through the arcuate nucleus and distribute the rich supply of hormones produced by the arcuate nucleus to the body.
In the arcuate nucleus, or the ARC, there are 2 populations of neurons; POMC/CART cells (proopiomelanocortin/cocaine and amphetamine-regulated transcript) and NPY/AgRP (neuropeptide Y/agouti-related protein) cells.
These neuronal cell bodies respond to fluctuating levels of insulin and leptin. In addition, they also control the inhibition and secretion of each other. The POMC/CART cells inhibit the activity of the NPY/AgRP cells, and vice versa.
Both cell bodies send extend their axons to other areas of the hypothalamus, expanding their circuitry to other areas of the brain. The insulin and leptin hormones enter the brain through the third ventricle and stimulate the POMC/CART cells, which release additional chemical signals to other areas of the brain. The presence of insulin and leptin inhibits NPY/AgRP cells, cutting off the circuitry that allows them to communicate with other neural structures for a period of time.
These neuronal cell bodies are referred to as NPY/AgRP neurons, as they release two different chemical messengers when stimulated — neuropeptide Y and agouti-related protein.
When insulin and leptin levels are high, the hormones inhibit these cells, cutting off the production of these two chemical messengers. However, when there are very low levels of insulin or leptin, neurons release NPY and AgRP messengers.
On the other hand, these cell bodies are referred to as POMC/CART neurons and release alpha melanocyte-stimulating hormone (MSH), an intermediate product of pro-opiomelanocortin (POMC) proteins. When stimulated, these neurons also release cocaine and amphetamine-regulated transcript proteins, which stimulate endogenous opioid receptors, which bind with compounds produced naturally in the body, such as endorphins.
These neurons undergo a similar process as NPY/AgRP neurons, however, in the opposite direction. When the blood sugar increases, and insulin and leptin increase, the POMC/CART neurons are stimulated and release the respective hormones.
aMSH and CART are appetite suppressants. When insulin and leptin levels are high, these hormones are produced, and your appetite decreases. When they are low, these hormones are not produced.
Orexigenic Hormones and Neurotransmitters
Hormones and neurotransmitters that are orexigenic stimulate our appetite and are released when the stomach is empty. There are dozens of orexigenic hormones, but 5 main ones take precedence:
NPY (neuropeptide Y): potent appetite stimulant; released when insulin and leptin are low
AgRP (agouti-related protein): potent appetite stimulant; released when insulin and leptin are low
Ghrelin: released by the stomach itself when it is physically empty, and also serves as a hunger signal to the brain
Progesterone: a steroid hormone, produced in the ovaries at high levels when a woman is pregnant or in the latter half of the menstrual cycle, and stimulates appetite to ensure that enough nutrition is being acquired to support herself and the (possible) offspring.
Androgens: a steroid hormone produced in the testes and both adrenal glands in males. The presence of androgens is one of the reasons that, on average, males can eat more food than females.
Anorexigenic Hormones and Neurotransmitters
On the other hand, anorexigenic hormones and neurotransmitters act as appetite suppressants. When the levels of these chemical messengers are increased, you feel full and your appetite is suppressed. Although there are many, 5 of them play the largest role in appetite suppression:
Insulin: hormone produced in the pancreas that allows for the uptake of glucose in the bloodstream to be utilized by cells, lowering blood sugar
Leptin: hormone produced by the adipose cells that sends satiety cues to the brain
aMSH (alpha melanocyte-stimulating hormone): potent appetite suppressant; released when insulin and leptin are high
CART (cocaine and amphetamine-regulated transcript): potent appetite suppressant; released when insulin and leptin are high
GLP-1 (glucagon-like peptide-1): a peptide hormone which induces satiety cues and stimulates glucose uptake by cells
A Well-Regulated Cycle
The well-regulated cycle takes into account many assumptions. In order for our appetite to work in this manner, we have to assume reliable and constantly available food sources, that all critical biological processes and running normally, regular hormonal secretion, that the body can use and store energy, signal to the brain that it is full, and consequently reduce an individual’s appetite.
The cycle starts with a meal. As you are eating, the blood glucose levels increase as the food is broken down and the glucose is liberated. Depending on the food being consumed, this process might be a very fast or lengthy process.
The increase in blood glucose signals to the pancreas, and the beta cells begin to secrete insulin, which in turn, lowers the blood glucose. When the blood glucose lowers, your body feels full, and you stop eating.
After some time, the insulin levels drop, causing you to once again, be hungry.
However, this cycle functions on many variables. For one, it relies on the consistent expectation that if you are hungry, food will be available. It also relies on the assumption that if you are full, you will stop eating, without overriding satiety cues.
However, we override satiety cues very often. While we might not do so when eating baby carrots, we most commonly do when eating desserts, which are high in both sugar and fat.
When you continue to eat, whilst overriding satiety cues, then your blood glucose remains elevated instead of dropping, which confuses your pancreas.
The role of your pancreas in regulating blood sugar is to monitor sugar release in your blood and release insulin. After the pancreas secretes insulin, normally, your blood glucose should drop. However, when it doesn’t, the pancreas is confused because it didn’t receive the expected response.
Usually, when this happens, the pancreas responds by secreting more insulin. Eventually, you will, and the blood glucose levels drop like normal.
However, if you consistently ignore your satiety cues and eat beyond them, it can be extremely harmful to the body over an extended period of time. When blood glucose consistently stays high, your pancreas gets extremely confused, and the beta cells become exhausted as they are unable to produce enough insulin. When your body is exposed to insulin all the time, it develops a resistance to insulin, eventually leading to the development of Type 2 Diabetes.
However, there are also many medical situations where appetite does not work normally. In some of these, we understand the underlying reasons, but for others, we do not. However, in all, we can observe how an individual’s lifestyle changes to alter their metabolism.
The most extreme case of this is Prader-Willi Syndrome, a genetic disorder in which an individual experiences constant hunger, leading to obesity and other behavioral problems.
Researchers have been able to attribute up to 75% of the foundation of the disease due to the deletion of a large region of the paternal copy of Chromosome 15.
When individuals with Prader Willi are born, they are smaller than usual. However, once they grow into adolescence, they develop an insatiable appetite due to elevated ghrelin secretion. Normally, ghrelin is only released when the stomach is empty, however, Prader Willi results in a dysregulation of ghrelin, one of our strongest orexigenic hormones.
Individuals with Prader Willi feel extreme hunger all the time and act upon this by eating constantly. This proves to be quite dangerous when we consider our environment in a modern world, where we have constant access to food. The strength of hunger signals sent to the brain can not only lead to obesity, but an individual can consume food to the point where their stomach can rupture. Therefore, most individuals with Prader Willi are most often institutionalized or carefully monitored.
There are certain natural mutations in our genes that also change how our bodies regulate our appetite. A study conducted by researchers at Cambridge recruited almost half a million individuals and sequenced their genes, focusing on the genes that encode for the receptor for MSH, released by POMC/CART neurons. These hormones bind to a receptor called MC4R (melanocortin-4 receptor).
This receptor quite literally allows you to feel full.
Hormones are chemical molecules, but they serve no function if they are unable to bind to a receptor.
In this study, researchers looked for natural variations in the gene that codes for the MSH receptor. Due to the complexity of our species, we all have subtle variations in our genetic makeup. Point mutations in our DNA can still make fully functioning receptors. However, mutations can sometimes lead to differences in the way the receptor will function.
The researchers found 61 different natural variations of the gene that codes for the MC4R receptor. This number is normal; it’s representative of our biological diversity. However, some of these variations lead to a loss of function.
Even if the gene to encode the receptor is there, a mutated gene might encode for a receptor that doesn’t work normally. For example, one mutation codes for a misshapen receptor, which causes the hormone to bind with the receptor poorly, or only binds for a short period of time. Some mutations leave the receptor with less than optimal function, and some with a complete loss of function. This results in an individual who loses their ability to be completely full; they might tend to feel hungry more frequently and might have stronger hunger signals, leading to more appetite stimulation.
However, what proved to be even more interesting about this study was that researchers found in a small subset of the population, individuals have mutations that lead to a gain of function of the receptor, leading it to work at a higher level than it should. This results in an individual who feels full more consistently and is less likely to overconsume even when food is readily available, which reduces their risk for obesity, a high BMI, diabetes, heart disease, and much more.
Our current landscape has changed the function of our core biological behavior. The convenience of our current landscape has changed our neural mechanisms to operate on a completely different level than our biological needs.
Our bodies still operate on the basic biological drives as they did millions of years ago.
The convenience of our lives does not optimize for our basic biology. It is up to us to control our lifestyle and use our biochemistry to our advantage.
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